Quinazoline derivatives

ABSTRACT

Novel quinazolinamide derivatives of the formula (I), in which R 1 -R 4  and X have the meanings indicated in Claim  1 , are HSP90 inhibitors and can be used for the preparation of a medicament for the treatment of diseases in which the inhibition, regulation and/or modulation of HSP90 plays a role.

BACKGROUND OF THE INVENTION

The invention was based on the object of finding novel compounds havingvaluable properties, in particular those which can be used for thepreparation of medicaments.

The present invention relates to compounds in which the inhibition,regulation and/or modulation of HSP90 plays a role, furthermore topharmaceutical compositions which comprise these compounds, and to theuse of the compounds for the treatment of diseases in which HSP90 playsa role.

The correct folding and conformation of proteins in cells is ensured bymolecular chaperones and is critical for the regulation of theequilibrium between protein synthesis and degradation. Chaperones areimportant for the regulation of many central functions of cells, suchas, for example, cell proliferation and apoptosis (Jolly and Morimoto,2000; Smith et al., 1998; Smith, 2001).

Heat Shock Proteins (HSPs)

The cells of a tissue react to external stress, such as, for example,heat, hypoxia, oxidative stress, or toxic substances, such as heavymetals or alcohols, with activation of a number of chaperones which areknown under the term “heat shock proteins” (HSPs).

The activation of HSPs protects the cell against damage initiated bysuch stress factors, accelerates the restoration of the physiologicalstate and results in a stress-tolerant state of the cell.

Besides this originally discovered protective mechanism promoted by HSPsagainst external stress, further important chaperone functions have alsobeen described in the course of time for individual HSPs under normalstress-free conditions. Thus, various HSPs regulate, for example,correct folding, intracellular localisation and function or regulateddegradation of a number of biologically important proteins of cells.

HSPs form a gene family with individual gene products whose cellularexpression, function and localisation differs in different cells. Thenaming and classification within the family is carried out on the basisof their molecular weight, for example HSP27, HSP70, and HSP90.

Some human diseases are based on incorrect protein folding (see review,for example, Tytell et al., 2001; Smith et al., 1998). The developmentof therapies which engages in the mechanism of the chaperone-dependentprotein folding could therefore be useful in such cases. For example,incorrectly folded proteins result in aggregation of protein withneurodegenerative progression in the case of Alzheimer's disease, priondiseases or Huntington's syndrome. Incorrect protein folding may alsoresult in loss of wild-type function, which can have the consequence ofincorrectly regulated molecular and physiological function.

HSPs are also ascribed great importance in tumour diseases. There are,for example, indications that the expression of certain HSPs correlateswith the stage of progression of tumours (Martin et al., 2000; Conroy etal., 1996; Kawanishi et al., 1999; Jameel et al., 1992; Hoang et al.,2000; Lebeau et al., 1991).

The fact that HSP90 plays a role in a number of central oncogenicsignalling pathways in the cell and certain natural products havingcancer-inhibiting activity target HSP90 has led to the concept thatinhibition of the function of HSP90 would be sensible in the treatmentof tumour diseases. An HSP90 inhibitor,17-allylamino-17-demethoxygeldanamycin (17AAG), a derivative ofgeldanamycin, is currently undergoing clinical trials.

HSP90

HSP90 represents approximately 1-2% of the total cellular protein mass.It is usually in the form of a dimer in the cell and is associated witha multiplicity of proteins, so-called co-chaperones (see, for example,Pratt, 1997). HSP90 is essential for the vitality of cells (Young etal., 2001) and plays a key role in the response to cellular stress byinteraction with many proteins whose native folding has been modified byexternal stress, such as, for example, heat shock, in order to restorethe original folding or to prevent aggregation of the proteins (Smith etal., 1998).

There are also indications that HSP90 is of importance as buffer againstthe effects of mutations, presumably through correction of incorrectprotein folding caused by the mutation (Rutherford and Lindquist, 1998).

In addition, HSP90 also has a regulatory importance. Under physiologicalconditions, HSP90, together with its homologue in the endoplasmaticreticulum, GRP94, plays a role in the cell balance for ensuring thestability of the conformation and maturing of various client keyproteins. These can be divided into three groups: receptors for steroidhormones, Ser/Thr or tyrosine kinases (for example ERBB2, RAF-1, CDK4and LCK) and a collection of various proteins, such as, for example,mutated p53 or the catalytic subunit of telomerase hTERT. Each of theseproteins takes on a key role in the regulation of physiological andbiochemical processes of cells. The preserved HSP90 family in humansconsists of four genes, cytosolic HSP90α, the inducible HSP90β isoform(Hickey et al., 1989), GRP94 in the endoplasmatic reticulum (Argon etal., 1999) and HSP75/TRAP1 in the mitochondrial matrix (Felts et al.,2000). It is assumed that all members of the family have a similar modeof action, but, depending on their localisation in the cell, bind todifferent client proteins. For example, ERBB2 is a specific clientprotein of GRP94 (Argon et al., 1999), while the type 1 receptor oftumour necrosis factor (TNFR1) or the retinoblastoma protein (Rb) havebeen found to be clients of TRAP1 (Song et al., 1995; Chen et al.,1996).

HSP90 is involved in a number of complex interactions with a largenumber of client proteins and regulatory proteins (Smith, 2001).Although precise molecular details have not yet been clarified,biochemical experiments and investigations with the aid of X-raycrystallography in recent years have increasingly been able to decipherdetails of the chaperone function of HSP90 (Prodromou et al., 1997;Stebbins et al., 1997). Accordingly, HSP90 is an ATP-dependent molecularchaperone (Prodromou et al, 1997), with dimerisation being important forATP hydrolysis. The binding of ATP results in the formation of atoroidal dimer structure, in which the two N-terminal domains come intoclose contact with one another and act as a switch in the conformation.(Prodromou and Pearl, 2000).

Known HSP90 Inhibitors

The first class of HSP90 inhibitors to be discovered were benzoquinoneansamycins with the compounds herbimycin A and geldanamycin. Originally,the reversion of the malignant phenotype in fibroblasts which had beeninduced by transformation with the v-Src oncogene was detected with them(Uehara et al., 1985).

Later, a strong antitumoural activity was demonstrated in vitro (Schulteet al., 1998) and in vivo in animal models (Supko et al., 1995).

Immune precipitation and investigations on affinity matrices then showedthat the principal mechanism of action of geldanamycin involves bindingto HSP90 (Whitesell et al., 1994; Schulte and Neckers, 1998). Inaddition, X-ray crystallographic studies have shown that geldanamycincompetes for the ATP binding site and inhibits the intrinsic ATPaseactivity of HSP90 (Prodromou et al., 1997; Panaretou et al., 1998). Thisprevents the formation of the multimeric HSP90 complex, with itsproperty of functioning as chaperone for client proteins. As aconsequence, client proteins are degraded via the ubiquitin-proteasomepathway.

The geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin(17AAG) showed an unchanged property in the inhibition of HSP90, thedegradation of client proteins and antitumoural activity in cellcultures and in xenograft tumour models (Schulte et al, 1998; Kelland etal, 1999), but had significantly lower liver cytotoxicity thangeldanamycin (Page et al. 1997). 17AAG is currently undergoing phaseI/II clinical trials.

Radicicol, a macrocyclic antibiotic, likewise exhibited revision of thev-Src and v-Ha-Ras-induced malignant phenotype of fibroblasts (Kwon etall 1992; Zhao et al, 1995). Radicicol degrades a large number of signalproteins as a consequence of HSP90 inhibition (Schulte et al., 1998).X-ray crystallographic studies have shown that radicicol likewise bindsto the N-terminal domain of HSP90 and inhibits the intrinsic ATPaseactivity (Roe et al., 1998).

As is known, antibiotics of the coumarine type bind to the ATP bindingsite of the HSP90 homologue DNA gyrase in bacteria. The coumarine,novobiocin, binds to the carboxy-terminal end of HSP90, i.e. to adifferent site in HSP90 than the benzoquinone-ansamycins and radicicol,which bind to the N-terminal end of HSP90. (Marcu et al., 2000b).

The inhibition of HSP90 by novobiocin results in degradation of a largenumber of HSP90-dependent signal proteins (Marcu et al., 2000a).

The degradation of signal proteins, for example ERBB2, was demonstratedusing PU3, an HSP90 inhibitor derived from purines. PU3 causes cellcycle arrest and differentiation in breast cancer cell lines (Chiosis etal., 2001).

HSP90 as Therapeutic Target

Due to the participation of HSP90 in the regulation of a large number ofsignalling pathways which are of crucial importance in the phenotype ofa tumour, and the discovery that certain natural products exert theirbiological effect through inhibition of the activity of HSP90, HSP90 iscurrently being tested as a novel target for the development of a tumourtherapeutic agent (Neckers et al., 1999).

The principal mechanism of action of geldanamycin, 17AAG, and radicicolincludes the inhibition of the binding of ATP to the ATP binding site atthe N-terminal end of the protein and the resultant inhibition of theintrinsic ATPase activity of HSP90 (see, for example, Prodromou et al.,1997; Stebbins et al., 1997; Panaretou et al., 1998). Inhibition of theATPase activity of HSP90 prevents the recruitment of co-chaperones andfavours the formation of an HSP90 heterocomplex, which causes clientproteins to undergo degradation via the ubiquitin-proteasome pathway(see, for example, Neckers et al., 1999; Kelland et al., 1999). Thetreatment of tumour cells with HSP90 inhibitors results in selectivedegradation of important proteins having fundamental importance forprocesses such as cell proliferation, regulation of the cell cycle andapoptosis. These processes are frequently deregulated in tumours (see,for example, Hostein et al., 2001).

An attractive rationale for the development of an inhibitor of HSP90 isthat a strong tumour-therapeutic action can be achieved by simultaneousdegradation of a plurality of proteins which are associated with thetransformed phenotype.

In detail, the present invention relates to compounds which inhibit,regulate and/or modulate HSP90, to compositions which comprise thesecompounds, and to methods for the use thereof for the treatment ofHSP90-induced diseases, such as tumour diseases, viral diseases, suchas, for example, hepatitis B (Waxman, 2002); immune suppression intransplants (Bijlmakers, 2000 and Yorgin, 2000); inflammation-induceddiseases (Bucci, 2000), such as rheumatoid arthritis, asthma, multiplesclerosis, type 1 diabetes, lupus erythematosus, psoriasis andinflammatory bowel disease; cystic fibrosis (Fuller, 2000); diseasesassociated with angiogenesis (Hur, 2002 and Kurebayashi, 2001), such as,for example, diabetic retinopathy, haemangiomas, endometriosis andtumour angiogenesis; infectious diseases; autoimmune diseases;ischaemia; promotion of nerve regeneration (Rosen et al., WO 02/09696;Degranco et al., WO 99/51223; Gold, U.S. Pat. No. 6,210,974 B1);fibrogenetic diseases, such as, for example, scleroderma, polymyositis,systemic lupus, cirrhosis of the liver, keloid formation, interstitialnephritis and pulmonary fibrosis (Strehlow, WO 02/02123).

The invention also relates to the use of the compounds according to theinvention for the protection of normal cells against toxicity caused bychemotherapy, and to the use in diseases where incorrect protein foldingor aggregation is a principal causal factor, such as, for example,scrapie, Creutzfeldt-Jakob disease, Huntington's or Alzheimer's(Sittler, Hum. Mol. Genet., 10, 1307, 2001; Tratzelt et al., Proc. Nat.Acad. Sci., 92, 2944, 1995; Winklhofer et al., J. Biol. Chem., 276,45160, 2001).

WO 01/72779 describes purine compounds and the use thereof for thetreatment of GRP94 (homologue or paralogue of HSP90)-induced diseases,such as tumour diseases, where the cancerous tissue includes a sarcomaor carcinoma selected from the group consisting of fibrosarcoma,myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma,angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumour,leiosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, syringocarcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinomas, bone marrow carcinoma, bronchogenic carcinoma,renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonic carcinoma, Wilm's tumour, cervical cancer,testicular tumour, lung carcinoma, small-cell lung carcinoma, bladdercarcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, haemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma,retinoblastoma, leukaemia, lymphoma, multiple myeloma, Waldenström'smacroglobulinaemia and heavy chain disease.

WO 01/72779 furthermore discloses the use of the compounds mentionedtherein for the treatment of viral diseases, where the viral pathogen isselected from the group consisting of hepatitis type A, hepatitis typeB, hepatitis type C, influenza, varicella, adenovirus, herpes simplextype I (HSV-I), herpes simplex type II (HSV-II), cattle plague,rhinovirus, echovirus, rotavirus, respiratory syncytial virus (RSV),papillomavirus, papovavirus, cytomegalovirus, echinovirus, arbovirus,huntavirus, Coxsackie virus, mumps virus, measles virus, rubella virus,polio virus, human immunodeficiency virus type I (HIV-I) and humanimmunodeficiency virus type II (HIV-II).

WO 01/72779 furthermore describes the use of the compounds mentionedtherein for GRP94 modulation, where the modulated biological GRP94activity causes an immune reaction in an individual, protein transportfrom the endoplasmatic reticulum, recovery from hypoxic/anoxic stress,recovery from malnutrition, recovery from heat stress, or combinationsthereof, and/or where the disorder is a type of cancer, an infectiousdisease, a disorder associated with disrupted protein transport from theendoplasmatic reticulum, a disorder associated withischaemia/reperfusion, or combinations thereof, where the disorderassociated with ischaemia/reperfusion is a consequence of cardiacarrest, asystolia and delayed ventricular arrhythmia, heart operation,cardiopulmonary bypass operation, organ transplant, spinal cord trauma,head trauma, stroke, thromboembolic stroke, haemorrhagic stroke,cerebral vasospasm, hypotonia, hypoglycaemia, status epilepticus, anepileptic fit, anxiety, schizophrenia, a neurodegenerative disorder,Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis(ALS) or neonatal stress.

Finally, WO 01/72779 describes the use of an effective amount of a GRP94protein modulator for the preparation of a medicament for changing asubsequent cellular reaction to an ischaemic state in a tissue site inan individual, by treatment of the cells at the tissue site with theGRP94 protein modulator in order that the GRP94 activity in cells isincreased to such an extent that a subsequent cellular reaction to anischaemic state is changed, where the subsequent ischaemic condition ispreferably the consequence of cardiac arrest, asystolia and delayedventricular arrhythmia, heart operation, cardiopulmonary bypassoperation, organ transplant, spinal cord trauma, head trauma, stroke,thromboembolic stroke, haemorrhagic stroke, cerebral vasospasm,hypotonia, hypoglycaemia, status epilepticus, an epileptic fit, anxiety,schizophrenia, a neurodegenerative disorder, Alzheimer's disease,Huntington's disease, amyotrophic lateral sclerosis (ALS) or neonatalstress, or where the tissue site is the donor tissue for a transplant.

A. Kamal et al. in Trends in Molecular Medicine, Vol. 10 No. 6 Jun.2004, describe therapeutic and diagnostic applications of HSP90activation, inter alia for the treatment of diseases of the centralnervous system and of cardiovascular diseases.

The identification of small compounds which specifically inhibit,regulate and/or modulate HSP90 is therefore desirable and an aim of thepresent invention.

It has been found that the compounds according to the invention andsalts thereof have very valuable pharmacological properties while beingwell tolerated.

In particular, they exhibit HSP90-inhibiting properties.

The present invention therefore relates to compounds according to theinvention as medicaments and/or medicament active ingredients in thetreatment and/or prophylaxis of the said diseases and to the use ofcompounds according to the invention for the preparation of apharmaceutical for the treatment and/or prophylaxis of the said diseasesand also to a process for the treatment of the said diseases whichcomprises the administration of one or more compounds according to theinvention to a patient in need of such an administration.

The host or patient may belong to any mammallian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, where they provide a model forthe treatment of a human disease.

PRIOR ART

-   WO 00/53169 describes HSP90 inhibition using coumarine or a    coumarine derivative.-   WO 03/041643 A2 discloses HSP90-inhibiting zearalanol derivatives.    HSP90-inhibiting indazole derivatives are known from WO 06/010595    and WO 02/083648.

FURTHER LITERATURE

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SUMMARY OF THE INVENTION

The invention relates to compounds of the formula I

in which

-   R¹, R² each, independently of one another, denote H, A, (CH₂)_(n)Het    or (CH₂)_(n)Ar,-   R¹ and R², together with the N atom to which they are bonded, also    denote a saturated, unsaturated or aromatic mono- or bicyclic    heterocycle, which may contain a further 1 to 3 N, O and/or S atoms    and which is unsubstituted or mono-, di- or trisubstituted by Hal,    A, (CH₂)_(n)Het, (CH₂)_(n)Ar, (CH₂)_(n)OH, (CH₂)_(n)OA,    (CH₂)_(n)NH₂, (CH₂)_(n)COOH, (CH₂)_(n)COOA, NHCOA, NA′COA, CONH₂,    CONHA, CONAA′, OC(═O)(CH₂)_(p)NH₂ and/or ═O (carbonyl oxygen),-   R³, R⁴ each, independently of one another, denote H, Hal, A,    (CH₂)_(n)Het, (CH₂)_(n)Ar, (CH₂)_(n)COHet or    (CH₂)_(n)C(═CH₂)CONR⁵R⁶,-   R³ and R⁴, together with the C atom to which they are bonded, also    denote a saturated or unsaturated monocyclic C3-C10-carbocycle,    which may contain a further 1 to 3 N, O and/or S atoms and which is    unsubstituted or mono-, di- or trisubstituted by Hal, A,    (CH₂)_(n)OH, (CH₂)_(n)OA, (CH₂)_(n)NH₂, (CH₂)_(n)COOH,    (CH₂)_(n)COOA, NHCOA, NA′COA, CONH₂, CONHA, CONAA′,    OC(═O)(CH₂)_(p)NH₂ and/or ═O (carbonyl oxygen),-   X denotes NR⁵R⁶, CONR⁵R⁶, CH₂NR⁵R⁶, COOR⁵, —OR⁵, CH₂OR⁵, COHet, Het,    CONH(CH₂)_(p)CN or CONH(CH₂)_(p)NR⁵R⁶,-   R⁵, R⁶ each, independently of one another, denote H, A, (CH₂)_(n)Het    or (CH₂)_(n)Ar,-   Ar denotes phenyl, naphthyl, tetrahydronaphthyl or biphenyl, each of    which is unsubstituted or mono-, di-, tri-, tetra- or    pentasubstituted by A, Hal, (CH₂)_(n)OA, (CH₂)_(n)OH, (CH₂)_(n)CN,    SA, SOA, SO₂A, NO₂, C≡CH, (CH₂)_(n)COOH, CHO, (CH₂)_(n)COOA, CONH₂,    CONHA, CONAA′, NHCOA, CH(OH)A, (CH₂)_(n)NH₂, (CH₂)_(n)NHA,    (CH₂)_(n)NAA′, (CH₂)_(n)NHSO₂A, SO₂NH(CH₂)_(n)NH₂, SO₂NH₂, SO₂NHA,    SO₂NAA′, CONH(CH₂)_(n)COOA, CONH(CH₂)_(n)COOH, NHCO(CH₂)_(n)COOA,    NHCO(CH₂)_(n)COOH, CONH(CH₂)_(n)NH₂, CONH(CH₂)_(n)NHA,    CONH(CH₂)_(n)NAA′, CONH(CH₂)_(n)CN and/or (CH₂)_(n)CH(NH₂)COOH,-   Het denotes a mono- or bicyclic saturated, unsaturated or aromatic    heterocycle having 1 to 4 N, O and/or S atoms, which may be    unsubstituted or mono-, di- or trisubstituted by A, OA, OH, phenyl,    SH, S(O)_(m)A, Hal, NO₂, CN, COA, COOA, COObenzyl, CONH₂, CONHA,    CONAA′, SO₂NH₂, NH₂, NHA, NAA′, NHCOA, NHSO₂A and/or ═O (carbonyl    oxygen),-   A, A′ each, independently of one another, denote unbranched or    branched alkyl having 1-10 C atoms, in which 1-3 non-adjacent CH₂    groups may be replaced by O, S, SO, SO₂, NH, NMe or Net, and/or, in    addition, 1-5H atoms may be replaced by F and/or Cl, or cyclic alkyl    having 3-8 C atoms,-   Hal denotes F, Cl, Br or I,-   n denotes 0, 1, 2, 3 or 4,-   p denotes 1, 2, 3 or 4,    and pharmaceutically usable salts and stereoisomers thereof,    including mixtures thereof in all ratios.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI and pharmaceutically usable salts, tautomers and stereoisomersthereof, characterised in that

a) for the preparation of compounds of the formula I in which X denotesCOOA,

a compound of the formula II

-   -   in which    -   R¹, R², R³ and R⁴ have the meanings indicated in Claim 1,    -   R denotes an amino-protecting group,    -   X denotes COOA,    -   and    -   A has the meaning indicated in Claim 1,        is reacted with a compound of the formula III        Y₃Si—N═C═N—SiY₃  III    -   in which    -   Y denotes alkyl having 1-4 C atoms,        or        b) a radical X is converted into another radical X by    -   i) hydrolysing an ester or    -   ii) converting an acid into an amide using an amine,        and/or a base or acid of the formula I is converted into one of        its salts.

Compounds of the formula I are also taken to mean the hydrates andsolvates of these compounds, furthermore pharmaceutically usablederivatives. The invention also relates to the stereoisomers (E, Zisomers) and the hydrates and solvates of these compounds. Solvates ofthe compounds are taken to mean adductions of inert solvent moleculesonto the compounds which form owing to their mutual attractive force.Solvates are, for example, mono- or dihydrates or alcoholates.

Pharmaceutically usable derivatives are taken to mean, for example, thesalts of the compounds according to the invention and also so-calledprodrug compounds.

Prodrug derivatives are taken to mean compounds of the formula I whichhave been modified with, for example, alkyl or acyl groups, sugars oroligopeptides and which are rapidly cleaved in the organism to give theeffective compounds according to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The expression “effective amount” means the amount of a medicament orpharmaceutical active ingredient that causes a biological or medicalresponse which is sought or desired, for example, by a researcher orphysician in a tissue, system, animal or human.

In addition, the expression “therapeutically effective amount” means anamount which, compared with a corresponding subject who has not receivedthis amount, has the following consequence:

improved healing treatment, healing, prevention or elimination of adisease, syndrome, condition, complaint, disorder or side effects oralso the reduction in the advance of a disease, complaint or disorder.

The term “therapeutically effective amount” also encompasses the amountswhich are effective for increasing normal physiological function.

The invention also relates to mixtures of the compounds of the formula Iaccording to the invention, for example mixtures of two diastereomers,for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.For all radicals which occur more than once, their meanings areindependent of one another.

Above and below, the radicals and parameters R¹, R², R³, R⁴ and X havethe meanings indicated for the formula I, unless expressly indicatedotherwise.

Carbamoyl denotes aminocarbonyl.

BOC or Boc denotes tert-butyloxycarbonyl.

A or A′ preferably denotes alkyl, is unbranched (linear) or branched,and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A or A′ particularlypreferably denotes methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl or tertbutyl, furthermore also pentyl, 1-, 2- or3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl,1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl.

A or A′ very particularly preferably denotes alkyl having 1, 2, 3, 4, 5or 6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl,pentafluoroethyl or 1,1,1-trifluoroethyl.

A, A′ also each denote, independently of one another, unbranched orbranched alkyl having 1-10 C atoms, in which 1-3 non-adjacent CH₂ groupsmay be replaced by O, S, SO, SO₂, NH, NMe, or NEt, such as, for example,2-methoxyethyl or 3-methylaminopropyl.

A or A′ also denotes cyclic alkyl(cycloalkyl). Cycloalkyl preferablydenotes cyclopropyl, cyclobutyl, cylopentyl, cyclohexyl or cycloheptyl.Cyclic alkyl furthermore preferably denotes cyclopropylmethyl,cyclopentylmethyl or cyclohexylmethyl.

Cycloalkylalkylene denotes, for example, cyclopropylmethylene orcyclohexylmethylene.

A,A′ particularly preferably denote, in each case independently of oneanother, unbranched or branched alkyl having 1-10 C atoms, in which 1-2non-adjacent CH₂ groups may be replaced by O, NH, NMe or NEt and/or, inaddition, 1-5H atoms may be replaced by F and/or Cl,

or cyclic alkyl having 3-8 C atoms.

R¹ and R², together with the N atom to which they are bonded, preferablydenote an unsubstituted saturated, unsaturated or aromatic mono- orbicyclic heterocycle, which may contain a further 1 to 2 N, O and/or Satoms, where the heterocycle is preferably selected from the grouppyrrolidine, piperidine, piperazine, morpholine, imidazolidine,oxazolidine, dihydroindole, isoindoline, tetrahydroquinoline,tetrahydroisoquinoline, tetrahydroquinoxaline.

Very particular preference is given to isoindoline(2,3-dihydroisoindole).

R³, R⁴, in each case independently of one another, preferably denote, H,A, (CH₂)_(n)COHet or (CH₂)_(n)C(═CH₂)CONR⁵R⁶.

R³, R⁴, in each case independently of one another, very particularlypreferably denote H, unbranched or branched alkyl having 1-6 C atoms, inwhich 1-5H atoms may be replaced by F and/or Cl, or4-methylpiperazin-1-ylcarbonylmethyl, H₂N—CO—C(═CH₂)CH₂.

R³, R⁴, together with the C atom to which they are bonded, furthermoreprefer ably also denote an unsubstituted saturated monocyclicC3-C6-carbocycle, which may contain a further 1 to 3 N, O and/or Satoms.

R³, R⁴, together with the C atom to which they are bonded, furthermoreparticularly preferably also denote an unsubstituted saturatedmonocyclic C3-, C4-, C5- or C6-carbocycle, which may contain a further 1to 2 N, O and/or S atoms.

X preferably denotes CONR⁵R⁶, COOR⁵, COHet, Het, CONH(CH₂)_(p)CN orCONH(CH₂)_(p)NR⁵R⁶.

X very particularly preferably denotes ethoxycarbonyl, carboxyl,carbamoyl, N-ethylcarbamoyl, N-tert-butylcarbamoyl,N,N-diethylcarbamoyl, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl,N-(2-hydroxyethyl)-N-methylcarbamoyl,N-(2-hydroxyethyl)-N-ethylcarbamoyl, pyrrolidin-1-ylcarbonyl,2-methylpyrrolidin-1-ylcarbonyl, 2,5-dimethylpyrrolidin-1-ylcarbonyl,N-methyl-carbamoyl, 4-methylpiperazin-1-ylcarbonyl,piperazin-1-ylcarbonyl,N-(3-methyl-3H-imidazol-4-ylmethyl)-N-methylcarbamoyl,N-(2-dimethylaminoethyl)-N-ethylcarbamoyl, N-propylcarbamoyl, N-butyl,carbamoyl, N-isobutylcarbamoyl, N-(carbamoylmethyl)carbamoyl,N-(2-cyano-ethyl)carbamoyl, N-(1,1,3,3-tetramethylbutyl)carbamoyl,4-methylpiperazin-1-yl.

R⁵, R⁶, in each case independently of one another, preferably denote H,A or (CH₂)_(n)Het.

Ar denotes, for example, phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-nitrophenyl, o-, m- or p aminophenyl, o-, m- orp-(N-methylamino)phenyl, o-, m- or p-(N-methylaminocarbonyl)phenyl, o-,m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- orp-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- orp-(N,N-dimethylamino)phenyl, o-, m- orp-(N,N-dimethylaminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl,o-, m- or p-(N,N-diethylamino) phenyl, o-, m- or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-(methylsulfonamido)phenyl, o-, m- or p-(methylsulfonyl)phenyl, o-, m-or p-cyanophenyl, o-, m- or p-acetylphenyl, o-, m- orp-aminosulfonylphenyl, o-, m- or p-carboxyphenyl, o-, m- orp-carboxymethylphenyl, o-, m- or p-carboxymethoxyphenyl, furtherpreferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-,2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-,3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-,2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-,2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or2,5-dimethyl-4-chlorophenyl.

Ar particularly preferably denotes phenyl which is unsubstituted ormono-, di-, tri-, tetra- or pentasubstituted by A, Hal and/or OA.

Irrespective of further substitutions, Het denotes, for example, 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2,4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thia diazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 1-, 3-, 4-, 5-,6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6-or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-,4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl,3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or8-2H-benzo-1,4-oxazinyl, further preferably 1,3-benzodioxol-5-yl,1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl or2,1,3-benzoxadiazol-5-yl.

The heterocyclic radicals may also be partially or fully hydrogenated.Het can thus also denote, for example, 2,3-dihydro-2-, -3-, -4- or-5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or-3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl,2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-di hydro-1-, -2-, -3-,-4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or-4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl,tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or-4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-,2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3-or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, further preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, isoindolinyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

Het preferably denotes pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl,imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl,piperazinyl, pyrazinyl, pyridazinyl, morpholinyl, azepanyl, azetidinyl,pyrrolidinyl or piperidinyl, each of which is unsubstituted or mono-,di- or trisubstituted by A, OA, OH, Hal, CN and/or ═O (carbonyl oxygen).

n preferably denotes 0, 1 or 2.

p preferably denotes 1 or 2.

The compounds of the formula I may have one or more chiral centres andcan therefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to Ih, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   in Ia R¹ and R², together with the N atom to which they are bonded,    denote an unsubstituted saturated, unsaturated or aromatic mono- or    bicyclic heterocycle, which may contain a further 1 to 2 N, O and/or    S atoms;-   in Ib R³, R⁴ each, independently of one another, denote H, A,    (CH₂)_(n)COHet or (CH₂)_(n)C(═CH₂)CONR⁵R⁶;-   in Ic R³ and R⁴, together with the C atom to which they are bonded,    also denote an unsubstituted saturated monocyclic C3-C6-carbocycle,    which may contain a further 1 to 3 N, O and/or S atoms;-   in Id X denotes CONR⁵R⁶, COOR⁵, COHet, Het, CONH(CH₂)_(p)CN or    CONH(CH₂)_(p)NR⁵R⁶;-   in Ie R⁵, R⁶ each, independently of one another, denote H, A or    (CH₂)_(n)Het;-   in If Het denotes pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl,    imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl,    piperazinyl, pyrazinyl, pyridazinyl, morpholinyl, azepanyl,    azetidinyl, pyrrolidinyl or piperidinyl, each of which is    unsubstituted or mono-, di- or trisubstituted by A, OA, OH, Hal, CN    and/or ═O (carbonyl oxygen);-   in Ig A, A′ each, independently of one another, denote unbranched or    branched alkyl having 1-10 C atoms, in which 1-2 non-adjacent CH₂    groups may be replaced by O, NH, NMe or NEt, and/or, in addition,    1-5H atoms may be replaced by F and/or Cl,    -   or cyclic alkyl having 3-8 C atoms;-   in Ih R¹ and R², together with the N atom to which they are bonded,    denote an unsubstituted saturated, unsaturated or aromatic mono- or    bicyclic heterocycle, which may contain a further 1 to 2 N, O and/or    S atoms,    -   R³, R⁴ each, independently of one another, denote H, A,        (CH₂)_(n)COHet or (CH₂)_(n)C(═CH₂)CONR⁵R⁶,    -   R³ and R⁴, together with the C atom to which they are bonded,        also denote an unsubstituted saturated monocyclic        C3-C6-carbocycle, which may contain a further 1 to 3 N, O and/or        S atoms,    -   X denotes CONR⁵R⁶, COOR⁵, COHet¹, Het¹, CONH(CH₂)_(p)CN or        CONH(CH₂)_(p)NR⁵R⁶,    -   Het denotes pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl,        imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl,        thiazolyl, piperazinyl, pyrazinyl, pyridazinyl, morpholinyl,        azepanyl, azetidinyl, pyrrolidinyl or piperidinyl, each of which        is unsubstituted or mono-, di- or trisubstituted by A, OA, OH,        Hal, CN and/or ═O (carbonyl oxygen),    -   A, A′ each, independently of one another, denote unbranched or        branched alkyl having 1-10 C atoms, in which 1-2 non-adjacent        CH₂ groups may be replaced by O, NH, NMe or NEt, and/or, in        addition, 1-5H atoms may be replaced by F and/or Cl,        -   or cyclic alkyl having 3-8 C atoms,    -   Hal denotes F, Cl, Br or I,    -   n denotes 0, 1, 2, 3 or 4,    -   p denotes 1, 2, 3 or 4;        and pharmaceutically usable salts, tautomers and stereoisomers        thereof, including mixtures thereof in all ratios.

The compounds according to the invention and also the starting materialsfor their preparation are, in addition, prepared by methods known perse, as described in the literature (for example in the standard works,such as Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use may also be made here of variants known per se which are notmentioned here in greater detail.

If desired, the starting materials can also be formed in situ by notisolating them from the reaction mixture, but instead immediatelyconverting them further into the compounds according to the invention.

The starting compounds are generally known. If they are novel, however,they can be prepared by methods known per se.

Compounds of the formula I can preferably be obtained by reacting acompound of the formula II with a compound of the formula III.

In the compounds of the formula II, R denotes an amino-protecting group,preferably tert-butyloxycarbonyl (BOC).

The reaction is carried out with addition of fluorides, preferablycaesium fluoride.

The reaction is carried out by methods which are known to the personskilled in the art.

Reaction is initially carried out in a suitable solvent.

Examples of suitable solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

The solvent is particularly preferably acetonitrile or DMF.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about 0° and150°, normally between 15° and 120°, particularly preferably between 20°and 60° C.

The term “amino-protecting group” is known in general terms and relatesto groups which are suitable for protecting (blocking) an amino groupagainst chemical reactions, but which are easily removable after thedesired chemical reaction has been carried out elsewhere in themolecule. Typical of such groups are, in particular, unsubstituted orsubstituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since theamino-protecting groups are removed after the desired reaction (orreaction sequence), their type and size are, in addition, not crucial;however, preference is given to those having 1-20, in particular 1-8, Catoms. The term “acyl group” is to be understood in the broadest sensein connection with the present process. It includes acyl groups derivedfrom aliphatic, araliphatic, aromatic or heterocyclic carboxylic acidsor sulfonic acids, and, in particular, alkoxycarbonyl, aryloxycarbonyland especially aralkoxycarbonyl groups. Examples of such acyl groups arealkanoyl, such as acetyl, propionyl, butyryl; aralkanoyl, such asphenylacetyl; aroyl, such as benzoyl or toluyl; aryloxyalkanoyl, such asPOA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, BOC (tert.-butyloxycarbonyl),2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ (“carbobenzoxy”),4-methoxybenzyloxycarbonyl, FMOC; arylsulfonyl, such as Mtr. Preferredamino-protecting groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyland acetyl.

The compounds of the formula I are liberated from their functionalderivatives using—depending on the protecting group used—for example,strong acids, advantageously using TFA or perchloric acid, but alsousing other strong inorganic acids, such as hydrochloric acid orsulfuric acid, strong organic carboxylic acids, such as trichloroaceticacid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid. Thepresence of an additional inert solvent is possible, but is not alwaysnecessary. Suitable inert solvents are preferably organic, for examplecarboxylic acids, such as acetic acid, ethers, such as tetrahydrofuranor dioxane, amides, such as DMF, halogenated hydrocarbons, such asdichloromethane, furthermore also alcohols, such as methanol, ethanol orisopropanol, and water. Mixtures of the above-mentioned solvents arefurthermore suitable. TFA is preferably used in excess without additionof a further solvent, perchloric acid in the form of a mixture of aceticacid and 70% perchloric acid in the ratio 9:1. The reaction temperaturesfor the cleavage are advantageously between about 0 and about 50°, workpreferably being carried out between 15 and 30° (room temperature).

The BOC, OBut and Mtr groups can, for example, preferably be cleaved offusing TFA in dichloromethane or using approximately 3 to 5N HCl indioxane at 15-30°, the FMOC group using an approximately 5 to 50%solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°.

Hydrogenolytically removable protecting groups (for example CBZ, benzylor the liberation of the amidino group from the oxadiazole derivativethereof) can be cleaved off, for example, by treatment with hydrogen inthe presence of a catalyst (for example a noble-metal catalyst, such aspalladium, advantageously on a support, such as carbon). Suitablesolvents here are those indicated above, in particular, for example,alcohols, such as methanol or ethanol, or amides, such as DMF. Thehydrogenolysis is generally carried out at temperatures between about 0and 100° and pressures between about 1 and 200 bar, preferably at 20-30°and 1-10 bar. Hydrogenolysis of the CBZ group succeeds well, forexample, on 5 to 10% Pd/C in methanol or using ammonium formate (insteadof hydrogen) on Pd/C in methanol/DMF at 20-30°.

It is furthermore possible to convert a compound of the formula I intoanother compound of the formula I by, for example, reducing nitro groupsto amino groups, for example by hydrogenation on Raney nickel orPd/carbon in an inert solvent, such as methanol or ethanol, and/orconverting an ester group into a carboxyl group or esterifying carboxylgroups by reaction with alcohols and/or converting carboxyl groups oracid chlorides into an acid amide by reaction with an amine.

Ester can be saponified, for example, using acetic acid or using NaOH orKOH in water, water/THF or water/dioxane at temperatures between 0 and100°. Furthermore, free amino and/or hydroxyl groups can be acylated ina conventional manner using an acid chloride or anhydride or alkylatedusing an unsubstituted or substituted alkyl halide, advantageously in aninert solvent, such as dichloromethane or THF, and/or in the presence ofa base, such as triethylamine or pyridine, at temperatures between −60and +30°.

Ether cleavages are carried out by methods which are known to the personskilled in the art.

The reaction is carried out in a suitable solvent, as indicated above,preferably by addition of boron tribromide.

The reaction is particularly preferably carried out in dichloromethaneat a reaction temperature between about −30° and 50°, normally between−20° and 20°, in particular between about −15° and about 0°.

The invention also relates to the compounds of the formula II

in which

-   R¹, R² each, independently of one another, denote H, A, (CH₂)_(n)Het    or (CH₂)_(n)Ar,-   R¹ and R², together with the N atom to which they are bonded, also    denote a saturated, unsaturated or aromatic mono- or bicyclic    heterocycle, which may contain a further 1 to 3 N, O and/or S atoms    and which is unsubstituted or mono-, di- or trisubstituted by Hal,    A, (CH₂)_(n)Het, (CH₂)_(n)Ar, (CH₂)_(n)OH, (CH₂)_(n)OA,    (CH₂)_(n)NH₂, (CH₂)_(n)COOH, (CH₂)_(n)COOA, NHCOA, NA′COA, CONH₂,    CONHA, CONAA′, OC(═O)(CH₂)_(p)NH₂ and/or ═O (carbonyl oxygen),-   R³, R⁴ each, independently of one another, denote H, Hal, A,    (CH₂)_(n)Het, (CH₂)_(n)Ar, (CH₂)_(n)COHet or    (CH₂)_(n)C(═CH₂)CONR⁵R⁶,-   R³ and R⁴, together with the C atom to which they are bonded, also    denote a saturated or unsaturated monocyclic C3-C10-carbocycle,    which may contain a further 1 to 3 N, O and/or S atoms and which is    unsubstituted or mono-, di- or trisubstituted by Hal, A,    (CH₂)_(n)OH, (CH₂)_(n)OA, (CH₂)_(n)NH₂, (CH₂)_(n)COOH,    (CH₂)_(n)COOA, NHCOA, NA′COA, CONH₂, CONHA, CONAA′,    OC(═O)(CH₂)_(p)NH₂ and/or ═O (carbonyl oxygen),-   R denotes tert-butyloxycarbonyl,-   X denotes COOR⁵,-   R⁵ denotes A,-   Ar denotes phenyl, naphthyl, tetrahydronaphthyl or biphenyl, each of    which is unsubstituted or mono-, di-, tri-, tetra- or    pentasubstituted by A, Hal, (CH₂)_(n)OA, (CH₂)_(n)OH, (CH₂)_(n)CN,    SA, SOA, SO₂A, NO₂, C≡CH, (CH₂)_(n)COOH, CHO, (CH₂)_(n)COOA, CONH₂,    CONHA, CONAA′, NHCOA, CH(OH)A, (CH₂)_(n)NH₂, (CH₂)_(n)NHA,    (CH₂)_(n)NAA′, (CH₂)_(n)NHSO₂A, SO₂NH(CH₂)_(n)NH₂, SO₂NH₂, SO₂NHA,    SO₂NAA′, CONH(CH₂)_(n)COOA, CONH(CH₂)_(n)COOH, NHCO(CH₂)_(n)COOA,    NHCO(CH₂)_(n)COOH, CONH(CH₂)_(n)NH₂, CONH(CH₂)_(n)NHA,    CONH(CH₂)_(n)NAA′, CONH(CH₂)_(n)CN and/or (CH₂)_(n)CH(NH₂)COOH,-   Het denotes a mono- or bicyclic saturated, unsaturated or aromatic    heterocycle having 1 to 4 N, O and/or S atoms, which may be    unsubstituted or mono-, di- or trisubstituted by A, OA, OH, phenyl,    SH, S(O)_(m)A, Hal, NO₂, CN, COA, COOA, COObenzyl, CONH₂, CONHA,    CONAA′, SO₂NH₂, NH₂, NHA, NAA′, NHCOA, NHSO₂A and/or ═O (carbonyl    oxygen),-   A, A′ each, independently of one another, denote unbranched or    branched alkyl having 1-10 C atoms, in which 1-3 non-adjacent CH₂    groups may be replaced by O, S, SO, SO₂, NH, NMe or NEt, and/or, in    addition, 1-5H atoms may be replaced by F and/or Cl, or cyclic alkyl    having 3-8 C atoms,-   Hal denotes F, Cl, Br or I,-   n denotes 0, 1, 2, 3 or 4,-   p denotes 1, 2, 3 or 4,    and salts thereof.

The meanings and the preferred meanings of the radicals indicated arethose as indicated above for the compounds of the formula I.

Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds according to theinvention are for the most part prepared by conventional methods. If thecompound according to the invention contains a carboxyl group, one ofits suitable salts can be formed by reacting the compound with asuitable base to give the corresponding base addition salt. Such basesare, for example, alkali metal hydroxides, including potassiumhydroxide, sodium hydroxide and lithium hydroxide; alkaline-earth metalhydroxides, such as barium hydroxide and calcium hydroxide; alkali metalalkoxides, for example potassium ethoxide and sodium propoxide; andvarious organic bases, such as piperidine, diethanolamine andN-methylglutamine. The aluminium salts of the compounds of the formula Iare likewise included. In the case of certain compounds of the formulaI, acid-addition salts can be formed by treating these compounds withpharmaceutically acceptable organic and inorganic acids, for examplehydrogen halides, such as hydrogen chloride, hydrogen bromide orhydrogen iodide, other mineral acids and corresponding salts thereof,such as sulfate, nitrate or phosphate and the like, and alkyl- andmonoarylsulfonates, such as ethanesulfonate, toluenesulfonate andbenzenesulfonate, and other organic acids and corresponding saltsthereof, such as acetate, trifluoroacetate, tartrate, maleate,succinate, citrate, benzoate, salicylate, ascorbate and the like.Accordingly, pharmaceutically acceptable acid-addition salts of thecompounds of the formula I include the following: acetate, adipate,alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate),bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate,caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate,digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate,ethanesulfonate, fumarate, galacterate (from mucic acid), galacturonate,gluco heptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate,hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide,isethionate, isobutyrate, lactate, lactobionate, malate, maleate,malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate,monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate,oxalate, oleate, palmoate, pectinate, persulfate, phenylacetate,3-phenylpropionate, phosphate, phosphonate, phthalate, but this does notrepresent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline-earth metal salts calciumand magnesium. Salts of the compounds according to the invention whichare derived from pharmaceutically acceptable organic non-toxic basesinclude salts of primary, secondary and tertiary amines, substitutedamines, also including naturally occurring substituted amines, cyclicamines, and basic ion exchanger resins, for example arginine, betaine,caffeine, chloroprocaine, choline,N,N′-dibenzylethylenediamine(benzathine), dicyclohexylamine,diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine,N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine,isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethanolamine, triethylamine, trimethylamine,tripropylamine and tris(hydroxy methyl)methylamine(tromethamine), butthis is not intended to represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

The acid-addition salts of basic compounds according to the inventionare prepared by bringing the free base form into contact with asufficient amount of the desired acid, causing the formation of the saltin a conventional manner. The free base can be regenerated by bringingthe salt form into contact with a base and isolating the free base in aconventional manner. The free base forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds according to the invention are formed with metals or amines,such as alkali metals and alkaline-earth metals or organic amines.Preferred metals are sodium, potassium, magnesium and calcium. Preferredorganic amines are N,N′-dibenzylethylenediamine, chloroprocaine,choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine andprocaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprises a compound according to theinvention in the form of one of its salts, in particular if this saltform imparts improved pharmacokinetic properties on the activeingredient compared with the free form of the active ingredient or anyother salt form of the active ingredient used earlier. Thepharmaceutically acceptable salt form of the active ingredient can alsoprovide this active ingredient for the first time with a desiredpharmacokinetic property which it did not have earlier and can even havea positive influence on the pharmacodynamics of this active ingredientwith respect to its therapeutic efficacy in the body.

Compounds according to the invention may be chiral owing to theirmolecular structure and may accordingly occur in various enantiomericforms. They can therefore exist in racemic or in optically active form.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theintermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the R andS forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid, suitably N-protected amino acids(for example N-benzoylproline or N-benzenesulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Suitableeluents for this purpose are aqueous or alcoholic solvent mixtures, suchas, for example, hexane/isopropanol/acetonitrile, for example in theratio 82:15:3.

The invention furthermore relates to the use of the compounds and/orphysiologically acceptable salts thereof for the preparation of amedicament (pharmaceutical composition), in particular by non-chemicalmethods. They can be converted into a suitable dosage form here togetherwith at least one solid, liquid and/or semi-liquid excipient or adjuvantand, if desired, in combination with one or more further activeingredients.

The invention furthermore relates to medicaments comprising at least onecompound according to the invention and/or pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and optionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.1 mg to 3 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the condition treated,the method of administration and the age, weight and condition of thepatient, or pharmaceutical formulations can be administered in the formof dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal)methods. Such formulations canbe prepared using all processes known in the pharmaceutical art by, forexample, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbent, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tabletting machine, giving lumps of non-uniform shape whichare broken up to form granules. The granules can be lubricated byaddition of stearic acid, a stearate salt, talc or mineral oil in orderto prevent sticking to the tablet casting moulds. The lubricated mixtureis then pressed to give tablets. The compounds according to theinvention can also be combined with a free-flowing inert excipient andthen pressed directly to give tablets without carrying out thegranulation or dry-pressing steps. A transparent or opaque protectivelayer consisting of a shellac sealing layer, a layer of sugar or polymermaterial and a gloss layer of wax may be present. Dyes can be added tothese coatings in order to be able to differentiate between differentdosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa pre specified amount of the compound. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds according to the invention and salts, solvates andphysiologically functional derivatives thereof can also be administeredin the form of liposome delivery systems, such as, for example, smallunilamellar vesicles, large unilamellar vesicles and multilamellarvesicles. Liposomes can be formed from various phospholipids, such as,for example, cholesterol, stearylamine or phosphatidylcholines.

The compounds according to the invention and the salts, solvates andphysiologically functional derivatives thereof can also be deliveredusing monoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds can also be coupled to solublepolymers as targeted medicament carriers. Such polymers may encompasspolyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenol or polyethylene oxidepolylysine, substituted by palmitoyl radicals. The compounds mayfurthermore be coupled to a class of biodegradable polymers which aresuitable for achieving controlled release of a medicament, for examplepolylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid,polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylatesand crosslinked or amphipathic block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary.

Injection solutions and suspensions prepared in accordance with therecipe can be prepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the presentinvention depends on a number of factors, including, for example, theage and weight of the human or animal, the precise condition requiringtreatment, and its severity, the nature of the formulation and themethod of administration, and is ultimately determined by the treatingdoctor or vet. However, an effective amount of a compound according tothe invention for the treatment is generally in the range from 0.1 to100 mg/kg of body weight of the recipient (mammal) per day andparticularly typically in the range from 1 to 10 mg/kg of body weightper day. Thus, the actual amount per day for an adult mammal weighing 70kg is usually between 70 and 700 mg, where this amount can beadministered as an individual dose per day or usually in a series ofpart-doses (such as, for example, two, three, four, five or six) perday, so that the total daily dose is the same. An effective amount of asalt or solvate or of a physiologically functional derivative thereofcan be determined as the fraction of the effective amount of thecompound according to the invention per se. It can be assumed thatsimilar doses are suitable for the treatment of other conditionsmentioned above.

The invention furthermore relates to medicaments comprising at least onecompound according to the invention and/or pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and at least one further medicament activeingredient.

Further medicament active ingredients are preferably chemotherapeuticagents, in particular those which inhibit angiogenesis and thus inhibitthe growth and spread of tumour cells; preference is given here to VEGFreceptor inhibitors, including robozymes and antisense which aredirected to VEGF receptors, and angiostatin and endostatin.

Examples of antineoplastic agents which can be used in combination withthe compounds according to the invention generally include alkylatingagents, antimetabolites; epidophyllotoxin; an antineoplastic enzyme; atopoisomerase inhibitor; procarbazin; mitoxantron or platinumcoordination complexes.

Antineoplastic agents are preferably selected from the followingclasses: anthracyclins, vinca medicaments, mitomycins, bleomycins,cytotoxic nucleosides, epothilones, discodermolides, pteridines,diynenes and podophyllotoxins.

Particular preference is given in the said classes to, for example,caminomycin, daunorubicin, aminopterin, methotrexate, methopterin,dichloromethotrexate, mitomycin C, porfiromycin, 5-fluorouracil,6-mercaptopurine, gemcitabine, cytosinarabinoside, podophyllotoxin orpodophyllotoxin derivatives, such as, for example, etoposide, etoposidephosphate or teniposide, melphalan, vinblastine, vincristine,leurosidine, vindesine, leurosine and paclitaxel. Other preferredantineoplastic agents are selected from the group estramustine,carboplatin, cyclophosphamide, bleomycin, gemcitabine, ifosamide,melphalan, hexamethylmelamine, thiotepa, cytarabin, idatrexate,trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11,topotecan, arabinosylcytosine, bicalutamide, flutamide, leuprolide,pyridobenzoindole derivatives, interferons and interleukins.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound according to the invention    and/or pharmaceutically usable derivatives, solvates and    stereoisomers thereof, including mixtures thereof in all ratios, and-   (b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound according tothe invention and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios,

and an effective amount of a further medicament active ingredient indissolved or lyophilised form.

Use

The present compounds are suitable as pharmaceutical active ingredientsfor mammals, in particular for humans, in the treatment of diseases inwhich HSP90 plays a role.

The invention thus relates to the use of the compounds according to theinvention, and pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, for thepreparation of a medicament for the treatment of diseases in which theinhibition, regulation and/or modulation of HSP90 plays a role.

The present invention encompasses the use of the compounds according tothe invention and/or physiologically acceptable salts and solvatesthereof for the preparation of a medicament for the treatment of tumourdiseases, such as, for example, fibrosarcoma, myxosarcoma, liposarcoma,chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,synovioma, mesothelioma, Ewing's tumour, leiosarcoma, rhabdomyosarcoma,colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer,prostate cancer, squamous cell carcinoma, basal cell carcinoma,adenocarcinoma, syringocarcinoma, sebaceous gland carcinoma, papillarycarcinoma, papillary adenocarcinomas, cystadenocarcinomas, bone marrowcarcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bileduct carcinoma, choriocarcinoma, seminoma, embryonic carcinoma, Wilm'stumour, cervical cancer, testicular tumour, lung carcinoma, small-celllung carcinoma, bladder carcinoma, epithelial carcinoma, glioma,astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma,haemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma,melanoma, neuroblastoma, retinoblastoma, leukaemia, lymphoma, multiplemyeloma, Waldenström's macroglobulinaemia and heavy chain disease; viraldiseases, where the viral pathogen is selected from the group consistingof hepatitis type A, hepatitis type B, hepatitis type C, influenza,varicella, adenovirus, herpes simplex type I (HSV-I), herpes simplextype II (HSV-II), cattle plague, rhinovirus, echovirus, rotavirus,respiratory syncytial virus (RSV), papillomavirus, papovavirus,cytomegalovirus, echinovirus, arbovirus, huntavirus, Coxsackie virus,mumps virus, measles virus, rubella virus, polio virus, humanimmunodeficiency virus type I (HIV-I) and human immunodeficiency virustype II (HIV-II);

for immune suppression in transplants; inflammation-induced diseases,such as rheumatoid arthritis, asthma, sepsis, multiple sclerosis, type 1diabetes, lupus erythematosus, psoriasis and inflammatory bowel disease;cystic fibrosis; diseases associated with angiogenesis, such as, forexample, diabetic retinopathy, haemangiomas, endometriosis, tumourangiogenesis; infectious diseases; autoimmune diseases; ischaemia;promotion of nerve regeneration; fibrogenetic diseases, such as, forexample, scleroderma, polymyositis, systemic lupus, cirrhosis of theliver, keloid formation, interstitial nephritis and pulmonary fibrosis;

The compounds according to the invention can inhibit, in particular, thegrowth of cancer, tumour cells and tumour metastases and are thereforesuitable for tumour therapy.

The present invention furthermore encompasses the use of the compoundsaccording to the invention and/or physiologically acceptable salts andsolvates thereof for the preparation of a medicament for the protectionof normal cells against toxicity caused by chemotherapy, and for thetreatment of diseases in which incorrect protein folding or aggregationis a principal causal factor, such as, for example, scrapie,Creutzfeldt-Jakob disease, Huntington's or Alzheimer's.

The invention also relates to the use of the compounds according to theinvention and/or physiologically acceptable salts and solvates thereoffor the preparation of a medicament for the treatment of diseases of thecentral nervous system, of cardiovascular diseases and cachexia.

In a further embodiment, the invention also relates to the use of thecompounds according to the invention and/or physiologically acceptablesalts and solvates thereof for the preparation of a medicament for HSP90modulation, where the modulated biological HSP90 activity causes animmune reaction in an individual, protein transport from theendoplasmatic reticulum, recovery from hypoxic/anoxic stress, recoveryfrom malnutrition, recovery from heat stress, or combinations thereof,and/or where the disorder is a type of cancer, an infectious disease, adisorder associated with disrupted protein transport from theendoplasmatic reticulum, a disorder associated withischaemia/reperfusion, or combinations thereof, where the disorderassociated with ischaemia/reperfusion is a consequence of cardiacarrest, asystolia and delayed ventricular arrhythmia, heart operation,cardiopulmonary bypass operation, organ transplant, spinal cord trauma,head trauma, stroke, thromboembolic stroke, haemorrhagic stroke,cerebral vasospasm, hypotonia, hypoglycaemia, status epilepticus, anepileptic fit, anxiety, schizophrenia, a neurodegenerative disorder,Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis(ALS) or neonatal stress.

In a further embodiment, the invention also relates to the use of thecompounds according to the invention and/or physiologically acceptablesalts and solvates thereof for the preparation of a medicament for thetreatment of ischaemia as a consequence of cardiac arrest, asystolia anddelayed ventricular arrhythmia, heart operation, cardiopulmonary bypassoperation, organ transplant, spinal cord trauma, head trauma, stroke,thromboembolic stroke, haemorrhagic stroke, cerebral vasospasm,hypotonia, hypoglycaemia, status epilepticus, an epileptic fit, anxiety,schizophrenia, a neurodegenerative disorder, Alzheimer's disease,Huntington's disease, amyotrophic lateral sclerosis (ALS) or neonatalstress.

Test Method for the Measurement of HSP90 Inhibitors

The binding of geldanamycin or 17-allylamino-17-demethoxygeldanamycin(17AAG) to HSP90 and competitive inhibition thereof can be utilised inorder to determine the inhibitory activity of the compounds according tothe invention (Carreras et al. 2003, Chiosis et al. 2002).

In the specific case, a radioligand filter binding test is used. Theradioligand used here is tritium-labelled 17-allylaminogeldanamycin,[3H]17AAG. This filter binding test allows a targeted search forinhibitors which interfere with the ATP binding site.

Material

Recombinant human HSP90α (E. coli expressed, 95% purity);

[3H]17AAG (17-allylaminogeldanamycin, [allylamino-2,3-³H. Specificactivity: 1.11×10¹² Bq/mmol (Moravek, MT-1717);

HEPES filter buffer (50 mM HEPES, pH 7.0, 5 mM MgCl2, BSA 0.01%)Multiscreen FB (1 μm) filter plate (Millipore, MAFBNOB 50).

Method

The 96-well microtitre filter plates are firstly irrigated and coatedwith 0.1% of polyethylenimine.

The test is carried out under the following conditions:

Reaction temperature 22° C.

Reaction time: 30 min., shaking at 800 rpm

Test volume: 50 μl

Final Concentrations:

50 mM HEPES HCl, pH 7.0, 5 mM MgCl2, 0.01% (w/v) of BSA

HSP90:1.5 μg/assay

[3H]17AAG: 0.08 μM.

At the end of the reaction, the supernatant in the filter plate isremoved by suction with the aid of a vacuum manifold (MultiscreenSeparation System, Millipore), and the filter is washed twice.

The filter plates are then measured in a beta counter (Microbeta,Wallac) with scintillator (Microscint 20, Packard).

“% of control” is determined from the “counts per minutes” values, andthe IC-50 value of a compound is calculated therefrom.

TABLE I HSP90 inhibition by compounds of the formula I according to theinvention Compound No. IC₅₀ “A1” A “A2” B “A3” B “A4” A “A5” A “A6” B“A7” B “A8” B “A9” B “A10” B “A11” B “A12” B “A13” B “A14” B “A15” B“A16” B “A17” B “A18” C “A19” B “A20” A “A21” A “A22” B “A23” B “A24” B“A25” B “A26” B “A27” B “A28” B “A29” A “A30” A “A31” A “A32” A “A33” A“A34” A “A35” A “A36” A “A37” A “A38” A “A39” A “A40” B “A41” A “A42” B“A43” A “A44” A “A45” A “A46” A “A47” A “A48” A “A49” “A50” B “A51”“A52” “A53” A “A54” B “A55” A “A56” A “A57” A ″ “A59” “A60” “A61” “A62”“A63” “A64” “A65” “A66” “A67” “A68” “A69” “A70” “A71” “A72” “A73” “A74”B “A75” “A76” B “A77” IC₅₀: 10 nM-1 μM = A 1 μM-10 μM = B >10 μM = C

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: water is added if necessary, thepH is adjusted, if necessary, to values between 2 and 10, depending onthe constitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate and evaporated, and the product is purifiedby chromatography on silica gel and/or by crystallisation.

LC-MS Conditions

The LC/MS measurements are carried out using a Hewlett Packard HP 1200series system having the following features: ion source: electrospray(positive mode); scan: 100-1000 m/e; fragmentation voltage: 60 V; gastemperature: 300° C., UV: 220 nm.

Flow rate: 2.4 ml/min.

Column: Chromolith SpeedROD RP-18e 50-4.6

Solvent: LiChrosolv grade from Merck KGaA

Solvent A: H2O (0.05% of formic acid)

Solvent B: ACN (0.04% of formic acid)

“Standard” Gradient:

4% of B→100% of B: 0 min to 2.8 min

100% of B: 2.8 min to 3.3 min

100% of B→4% of B: 3.3 min to 3.4 min

“Polar” Gradient:

1% of B→100% of B: 0 min to 3.5 min

100% of B: 3.5 min to 5 min

100% of B→10% of B: 5 min to 5.5 min

10% of B→1% of B: 5.5 min to 6 min

“Nonpolar” Gradient:

20% of B→100% of B: 0 min to 2.8 min

100% of B: 2.8 min to 3.3 min

100% of B→20% of B: 3.3 min to 3.4 min

If no further information is provided regarding the retention time,“standard” gradient is used.

EXAMPLE 1 Preparation of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetate (“A1”) and2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetic acid (“A2”)Step 1: Ethyl 2-[4-[[(2Z/E)-2-hydroxyiminoacetyl]amino]phenylacetate

18 g of chloral hydrate are dissolved in 100 ml of water, 27 g of Na₂SO₄are added, and the mixture is stirred at 23° C. for 10 min. A solutionof 20 g of ethyl 4-aminophenylacetate hydrochloride in 100 ml of wateris added to this solution. 19 g of hydroxylammonium chloride in 50 ml ofwater are added to the resultant suspension, and the mixture is stirredat 60° C. for 90 min. The mixture is subsequently allowed to cool,during which a precipitate deposits. This is filtered off, washed withwater and dried at 40° C. in vacuo. The mixture obtained was employed inthe following reaction without further purification.

Yield: 11.2 g (mixture of ethyl2-[4-[[(2Z/E)-2-hydroxyiminoacetyl]amino]-phenylacetate and2-[4-[[(2Z/E)-2-hydroxyiminoacetyl]amino]phenylacetic acid in the ratio1:1.7);

LC-MS retention time: 1.22 min (ethyl2-[4-[[(2Z/E)-2-hydroxyiminoacetyl]-amino]phenylacetate) and 0.51 min(2-[4-[[(2Z/E)-2-hydroxyiminoacetyl]-amino]phenylacetic acid).

Step 2: (2,3-Dioxo-2,3-dihydro-1H-indol-5-yl)acetic acid

11.6 g of the mixture obtained from step 1 are added in portions to 30ml of sulfuric acid (98%) at 50° C., during which the temperature risesto 120° C. When the addition is complete, the mixture is stirred for afurther 15 min and subsequently poured into 400 ml of ice-water. Theresultant precipitate is filtered off, washed with water. Drying at 40°C. in vacuo gives 8.1 g of (2,3-dioxo-2,3-dihydro-1H-indol-5-yl)aceticacid; LC-MS retention time: 1.11 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.48 (dd, J=8.0, 1.8, 1H),7.42 (d, J=1.2, 1H), 6.88 (d, J=8.0, 1H), 3.59 (s, 2H).

Step 3: Ethyl 2-(2,3-dioxoindolin-5-yl)acetate

4 g of (2,3-dioxo-2,3-dihydro-1H-indol-5-yl)acetic acid are dissolved in100 ml of ethanol, and 300 mg of toluene-4-sulfonic acid monohydrate areadded. The mixture is heated at 80° C. for 1 h, and the solvent issubsequently removed in vacuo. The residue is taken up in 100 ml ofwater and 100 ml of ethyl acetate and stirred at 60° C. for a further 12h. The mixture is neutralised using sodium hydrogencarbonate, and theorganic phase is separated off. The aqueous phase is washed a furthertwice with 100 ml of ethyl acetate each time. The combined organicphases are dried over sodium sulfate, filtered and evaporated to drynessin vacuo, giving 4.1 g of ethyl 2-(2,3-dioxoindolin-5-yl)acetate;

LC-MS retention time: 1.09 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.46 (dd, J=8.1, 1.8, 1H),7.40 (d, J=1.2, 1H), 6.87 (d, J=7.9, 1H), 4.06 (q, J=7.2, 2H), 3.63 (s,2H), 1.17 (t, J=7.1, 3H).

Step 4: tert-Butyl5-(2-ethoxy-2-oxoethyl)-2,3-dioxoindoline-1-carboxylate

520 mg of di-tert-butyl dicarbonate are added to 549 mg of ethyl2-(2,3-dioxoindolin-5-yl)acetate and 15 mg of 4-dimethylaminopyridine in20 ml of tetrahydrofuran, and the mixture is subsequently stirred at 23°C. for 12 h. The solvent is removed at 23° C. in vacuo, and the productis processed further directly;

LC-MS retention time: 2.02 min (“nonpolar” gradient).

Step 5: Ethyl2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]acetate

2.2 g of isoindoline are added to 5.9 g of tert-butyl5-(2-ethoxy-2-oxoethyl)-2,3-dioxoindoline-1-carboxylate in 100 ml oftetrahydrofuran, and the mixture is subsequently stirred at 23° C. for 1h. The solvent is removed in vacuo, and the residue is purified bycolumn chromatography, giving 4.9 g of ethyl2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]acetate;

LC-MS retention time: 2.50 min (“nonpolar” gradient).

Step 6: Ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetate (“A1”)

4.9 g of ethyl2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxo-acetyl)phenyl]acetateare dissolved in 100 ml of acetonitrile under argon. 1.7 g of caesiumfluoride are added, and 3 ml of bis(trimethylsilyl)carbodiimide areadded dropwise to the solution over the course of 5 min. The mixture isstirred at room temperature for 15 min, and 20 ml of dichloromethane arethen added. After addition of 20 ml of hydrochloric acid (1N), theproduct precipitates out as white solid.

Yield: 2.8 g (69%) of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-ylacetate;

LC-MS retention time: 1.49 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.95 (dd, J=10.7, 1.9, 2H),7.72 (d, J=8.6, 1H), 7.43 (d, J=7.5, 1H), 7.29 (dt, J=23.7, 7.3, 2H),7.20 (d, J=7.3, 1H), 5.02 (s, 2H), 4.75 (s, 2H), 4.05 (q, J=7.1, 2H),3.83 (s, 2H), 1.13 (t, J=7.1, 3H).

Step 7: 2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetic acid(“A2”)

2.7 g of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetate aredissolved in 40 ml of tetrahydrofuran, and 25 ml of 2N sodium hydroxidesolution are added. The mixture is stirred at 23° C. for 12 h,evaporated to dryness in vacuo, taken up in 10 ml of water and adjustedto pH 2 using 7 ml of 25% hydrochloric acid. The resultant precipitateis filtered off and dried in vacuo.

Yield: 2.0 g (80%) of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-acetic acid;

LC-MS retention time: 1.04 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.96 (d, J=7.0, 2H), 7.74-7.69(m, 1H), 7.44 (d, J=7.5, 1H), 7.30 (dt, J=23.5, 7.3, 2H), 7.21 (d,J=7.3, 1H), 5.02 (s, 2H), 4.76 (s, 2H), 3.76 (s, 2H).

EXAMPLE 2 Preparation of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetamide (“A3”)

100 mg of “A1” are dissolved in 40 ml of methanol, and 135 mg ofmagnesium nitride are added. The mixture is stirred at 80° C. for 12 h,cooled, diluted with 10 ml of water and adjusted to pH 2 using 25%hydrochloric acid. The resultant precipitate is filtered off andpurified by column chromatography. Yield: 18 mg (20%) of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetamide; LC-MSretention time: 0.74 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.98 (dd, J=8.7, 1.8, 1H),7.93 (d, J=1.4, 1H), 7.73 (d, J=8.5, 1H), 7.48 (d, J=7.3, 1H), 7.34 (dt,J=17.9, 6.9, 2H), 7.25 (d, J=7.3, 1H), 5.05 (s, 2H), 4.80 (s, 2H), 3.58(s, 2H).

The compound1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-5,5-difluoropentanamide(“A4”) is obtained analogously

Yield: 15 mg (16%); LC-MS retention time: 1.64 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] (dd, J=8.9, 1.9, 1H), 7.64 (d,J=1.8, 1H), 7.52-7.42 (m, 2H), 7.36-7.23 (m, 3H), 7.00 (s, 2H), 6.03(tt, J=57.0, 4.1, 1H), 4.99 (s, 2H), 4.67 (s, 2H), 3.52 (dd, J=8.5, 6.0,1H), 2.09-1.56 (m, 4H).

The compound1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclobutane-carboxamide(“A5”) is obtained analogously

Yield: 9 mg (10%); LC-MS retention time: 1.12 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.03 (dd, J=8.7, 2.0, 1H),7.99 (d, J=1.7, 1H), 7.78 (d, J=8.7, 1H), 7.48 (d, J=7.0, 1H), 7.40-7.29(m, 2H), 7.27 (d, J=7.6, 1H), 5.10 (s, 2H), 4.86 (s, 2H), 2.84-2.73 (m,2H), 2.45-2.37 (m, 2H), 1.97-1.69 (m, 2H).

EXAMPLE 3 Preparation of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethylacetamide(“A6”)

50 mg of “A2” are dissolved in 2 ml of ethylamine and irradiated in themicrowave (CEM Discover®) at max. 120° C. for 60 min. The mixture isevaporated to dryness in vacuo, the residue is taken up in DMSO andpurified by column chromatography. Yield: 8 mg (16%) of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethylacetamide;

LC-MS retention time: 1.53 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.99 (dd, J=8.6, 1.8, 1H),7.95 (d, J=1.2, 1H), 7.75 (d, J=8.5, 1H), 7.48 (d, J=7.2, 1H), 7.34 (dt,J=18.6, 6.9, 2H), 7.25 (d, J=7.3, 1H), 5.07 (s, 2H), 4.81 (s, 2H), 3.59(s, 2H), 3.07 (q, J=7.2, 2H), 0.99 (t, J=7.2, 3H)

EXAMPLE 4 Preparation of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-tert-butylacetamide(“A7”)

100 mg of “A2” are suspended in 3 ml of thionyl chloride and stirred at23° C. for 12 h. The mixture is evaporated to dryness in vacuo, and theresidue is taken up in 4 ml of tetrahydrofuran. This solution is addedto a solution of 35 μl of tert-butylamine and 46 μl ofN-ethyldiisopropylamine in 2 ml of tetrahydrofuran. After 2 h at 23° C.,the mixture is evaporated to dryness in vacuo, taken up in acetonitrileand purified by column chromatography. Yield: 32 mg (29%) of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-tert-butylacetamide;

LC-MS retention time: 1.77 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.98 (dd, J=8.6, 1.8, 1H),7.93 (d, J=1.3, 1H), 7.75 (d, J=8.6, 1H), 7.48 (d, J=7.5, 1H), 7.34 (dt,J=24.0, 7.2, 2H), 7.24 (d, J=7.5, 1H), 5.07 (s, 2H), 4.79 (s, 2H), 3.55(s, 2H), 1.20 (s, 9H).

EXAMPLE 5 Preparation of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N,N-diethylacetamide(“A8”)

119.7 mg of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU), 44.4 μl of diethylamine and 157.8 μl of4-methylmorpholine are added to a solution of 100 mg of “A2” in 1 ml ofdimethylformamide. The mixture is subsequently stirred at 25° C. for 12h. The mixture is evaporated to dryness in vacuo, taken up in 1 ml ofdimethyl sulfoxide and purified by chromatography (reversed phase HPLC).

Yield: 60 mg (52%) of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N,N-diethylacetamide;LC-MS retention time: 1.76 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.94 (dd, J=8.7, 1.7, 1H),7.90 (s, 1H), 7.73 (d, J=8.6, 1H), 7.48 (d, J=7.5, 1H), 7.34 (dt,J=23.3, 7.3, 2H), 7.25 (d, J=7.5, 1H), 5.05 (s, 2H), 4.78 (s, 2H), 3.88(s, 2H), 3.38 (q, J=7.1, 2H), 3.28 (q, J=7.0, 2H), 1.13 (t, J=7.2, 3H),1.00 (t, J=7.1, 3H).

The following compounds are obtained analogously:

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N,N-dimethylacetamide(“A9”)

LC-MS retention time: 1.50 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.89-7.84 (m, 2H), 7.71-7.67(m, 1H), 7.41 (d, J=7.5, 1H), 7.28 (dt, J=23.5, 7.2, 2H), 7.19 (d,J=7.5, 1H), 5.01 (s, 2H), 4.75 (s, 2H), 3.84 (s, 2H), 3.00 (s, 3H), 2.79(s, 3H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethyl-N-methylacetamide(“A10”)

LC-MS retention time: 1.59 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] δ 7.89-7.83 (m, 2H), 7.68 (dd,J=8.7, 2.5, 1H), 7.39 (d, J=7.5, 1H), 7.27 (dt, J=23.5, 7.2, 2H), 7.17(d, J=7.3, 1H), 5.00 (s, 2H), 4.74 (s, 2H), 3.87-3.76 (m, 2H), 3.40-3.23(m, 2H), 2.96-2.73 (m, 3H), 1.10-0.89 (m, 3H); rotational isomermixture.

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-(2-hydroxyethyl)-N-methylacetamide(“A11”)

LC-MS retention time: 1.38 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.92-7.82 (m, 2H), 7.70 (d,J=8.6, 1H), 7.43 (d, J=7.5, 1H), 7.30 (dt, J=23.1, 7.4, 2H), 7.21 (d,J=7.3, 1H), 5.01 (s, 2H), 4.76 (s, 2H), 3.96-3.84 (m, 2H), 3.54 (t,J=5.6, 2H), 3.44 (t, J=6.7, 2H), 3.32-3.29 (m, 2H), 1.12-0.93 (m, 3H);rotational isomer mixture.

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-(2-hydroxyethyl)-N-ethylacetamide(“A12”)

LC-MS retention time: 1.46 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.92-7.82 (m, 2H), 7.70 (d,J=8.6, 1H), 7.43 (d, J=7.5, 1H), 7.30 (dt, J=23.1, 7.4, 2H), 7.21 (d,J=7.3, 1H), 5.01 (s, 2H), 4.76 (s, 2H), 3.96-3.84 (m, 2H), 3.54 (t,J=5.6, 2H), 3.44 (t, J=6.7, 2H), 3.32-3.29 (m, 2H), 1.12-0.93 (m, 3H);rotational isomer mixture.

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-(2-dimethylaminoethyl)-N-ethylacetamide(“A59”)

LC-MS retention time: 1.26 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.99-7.91 (m, 2H), 7.76 (d,J=8.6, 1H), 7.47 (d, J=7.5, 1H), 7.34 (dt, J=23.5, 7.2, 2H), 7.25 (d,J=7.5, 1H), 5.07 (s, 2H), 4.81 (s, 2H), 3.96 (s, 2H), 3.63 (t, J=6.4,2H), 3.48 (q, J=7.0, 2H), 3.25 (t, J=6.5, 2H), 2.82 (s, 6H), 1.18 (t,J=7.1, 3H); rotational isomer mixture.

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-1-pyrrolidin-1-ylethanone(“A13”)

yield: 53 mg (46%); LC-MS retention time: 1.64 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.95 (dd, J=8.6, 1.7, 1H),7.92 (s, 1H), 7.74 (d, J=8.6, 1H), 7.47 (d, J=7.5, 1H), 7.34 (dt,J=23.5, 7.3, 2H), 7.25 (d, J=7.5, 1H), 5.06 (s, 2H), 4.79 (s, 2H), 3.83(s, 2H), 3.51 (t, J=6.8, 2H), 3.31 (t, J=6.8, 2H), 1.93-1.86 (m, 2H),1.78 (p, J=6.9, 2H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-1-(2-methylpyrrolidin-1-yl)ethanone(“A14”)

LC-MS retention time: 1.71 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.99-7.88 (m, 2H), 7.74 (dd,J=8.6, 3.7, 1H), 7.48 (d, J=7.5, 1H), 7.34 (dt, J=23.5, 7.2, 2H), 7.25(d, J=7.5, 1H), 5.05 (s, 2H), 4.79 (s, 2H), 4.25-3.74 (m, 3H), 3.59-3.29(m, 2H), 2.04-1.45 (m, 4H), 1.24-1.02 (m, 3H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-1-(2,5-dimethylpyrrolidin-1-yl)ethanone(“A15”)

LC-MS retention time: 1.81 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.96 (dd, J=8.6, 1.8, 1H),7.92 (d, J=1.3, 1H), 7.75 (d, J=8.6, 1H), 7.47 (d, J=7.5, 1H), 7.34 (dt,J=23.5, 7.2, 2H), 7.25 (d, J=7.5, 1H), 5.06 (s, 2H), 4.80 (s, 2H),4.22-4.11 (m, 1H), 3.99-3.88 (m, 2H), 3.82-3.76 (m, 1H), 2.07-1.87 (m,2H), 1.67-1.57 (m, 2H), 1.24-1.17 (m, 6H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-methylacetamide(“A16”)

LC-MS retention time: 1.39 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.99 (dd, J=8.7, 1.7, 1H),7.94 (s, 1H), 7.74 (d, J=8.6, 1H), 7.48 (d, J=7.5, 1H), 7.34 (dt,J=23.1, 7.2, 2H), 7.25 (d, J=7.3, 1H), 5.06 (s, 2H), 4.81 (s, 2H), 3.60(s, 2H), 2.58 (s, 3H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-1-(4-methylpiperazin-1-yl)ethanone(“A17”)

LC-MS retention time: 1.16 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.91 (dd, J=8.6, 1.8, 1H),7.88 (s, 1H), 7.75 (d, J=8.6, 1H), 7.48 (d, J=7.3, 1H), 7.34 (dt,J=22.7, 7.4, 2H), 7.26 (d, J=7.5, 1H), 5.05 (s, 2H), 4.82 (s, 2H),4.05-3.91 (m, 2H), 3.59-3.33 (m, 4H), 3.17-2.90 (m, 4H), 2.85 (s, 3H).

EXAMPLE 6 Preparation of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-1-piperazin-1-ylethanone(“A18”) Step 1:4-[2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetyl]-piperazine-1-tert-butylcarboxylate

The compound is obtained in accordance with the preceding process(Example 5). LC-MS retention time: 1.88 min.

Step 2:2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-1-piperazin-1-ylethanone

4-[2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetyl]piperazine-1-tert-butylcarboxylateis dissolved in 5 ml of dichloromethane/trifluoroacetic acid (1:1) andstirred at 23° C. for 60 min. The mixture is subsequently evaporated todryness in vacuo, taken up in 1 ml of DMSO and purified preparatively onthe reversed phase. Yield: 100 mg (84%); LC-MS retention time: 1.16 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.91 (dd, J=8.6, 1.8, 1H),7.88 (s, 1H), 7.76 (d, J=8.6, 1H), 7.48 (d, J=7.5, 1H), 7.34 (dt,J=22.6, 7.2, 2H), 7.26 (d, J=7.3, 1H), 5.05 (s, 2H), 4.81 (s, 2H), 3.97(s, 2H), 3.73 (d, J=42.5, 4H), 3.15 (d, J=37.0, 4H).

The following compounds are obtained analogously to Example 5:

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-methyl-N-[(3-methylimidazol-4-ylmethyl]acetamide(“A19”)

LC-MS retention time: 1.22 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 9.06 (s, 1H), 7.94 (dt, J=7.9,4.0, 1H), 7.92 (s, 1H), 7.75 (d, J=8.6, 1H), 7.66 (s, 1H), 7.48 (d,J=7.5, 1H), 7.34 (dt, J=23.3, 7.3, 2H), 7.25 (d, J=7.5, 1H), 5.05 (s,2H), 4.81 (s, 2H), 4.65 (s, 2H), 3.97 (d, J=17.8, 2H), 3.77 (s, 3H),3.07 (s, 3H).

1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-tert-butylcyclopropanecarboxamide(“A20”)

LC-MS retention time: 1.92 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.11 (s, 1H), 8.02-7.97 (m,1H), 7.77 (d, J=9.4, 1H), 7.46 (d, J=7.5, 1H), 7.34 (dt, J=14.9, 7.2,2H), 7.24 (d, J=7.3, 1H), 5.08 (s, 2H), 4.84 (s, 2H), 1.42-1.38 (m, 2H),1.16 (s, 9H), 1.06 (dd, J=6.9, 4.3, 2H).

1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethylcyclopropanecarboxamide(“A21”)

LC-MS retention time: 1.66 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.99 (dd, J=8.6, 1.9, 1H),7.92 (d, J=1.7, 1H), 7.73 (d, J=8.9, 1H), 7.45 (d, J=7.3, 1H), 7.36-7.26(m, 2H), 7.22 (d, J=7.3, 1H), 5.03 (s, 2H), 4.78 (s, 2H), 2.97 (q,J=7.1, 3H), 1.40-1.35 (m, 2H), 1.02 (dd, J=6.6, 4.0, 2H), 0.85 (t,J=7.2, 3H).

1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N,N-dimethylcyclopropanecarboxamide(“A22”)

LC-MS retention time: 1.50 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.76 (dd, J=8.9, 2.0, 1H),7.70 (d, J=8.7, 1H), 7.63 (d, J=1.7, 1H), 7.41 (d, J=7.3, 1H), 7.33-7.23(m, 2H), 7.19 (d, J=5.5, 1H), 5.00 (s, 2H), 4.78 (s, 2H), 2.73 (s, 6H),1.35-1.32 (m, 1H), 1.23-1.20 (m, 1H).

1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethyl-N-methylcyclopropanecarboxamide(“A23”)

LC-MS retention time: 1.69 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.81-7.60 (m, 3H), 7.40 (d,J=7.2, 1H), 7.33-7.22 (m, 2H), 7.18 (d, J=7.3, 1H), 4.98 (s, 2H), 4.77(s, 2H), 3.22 (q, J=7.1, 2H), 2.69 (s, 3H), 1.35-1.31 (m, 2H), 1.26-1.18(m, 2H), 0.95-0.84 (m, 3H).

1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N,N-diethylcyclopropanecarboxamide(“A24”)

LC-MS retention time: 1.79 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.78 (dd, J=8.9, 2.0, 1H),7.72 (d, J=8.9, 1H), 7.65 (d, J=1.8, 1H), 7.46 (d, J=7.2, 1H), 7.37-7.28(m, 2H), 7.23 (d, J=7.0, 1H), 4.98 (s, 2H), 4.78 (s, 2H), 3.21 (q,J=7.0, 4H), 1.36 (dd, J=6.8, 4.9, 2H), 1.24 (dd, J=6.9, 5.0, 2H),1.00-0.92 (m, 3H), 0.78-0.70 (m, 3H).

1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-(2-hydroxyethyl)-N-methylcyclopropanecarboxamide(“A25”)

LC-MS retention time: 1.48 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.76 (d, J=8.8, 1H), 7.70 (d,J=8.8, 2H), 7.40 (d, J=7.5, 1H), 7.27 (dt, J=22.2, 7.1, 2H), 7.19 (d,J=7.5, 1H), 5.00 (s, 2H), 4.79 (s, 2H), 3.53-3.44 (m, 2H), 3.35-3.25 (m,2H), 2.79 (s, 3H), 1.43-1.37 (m, 2H), 1.26-1.19 (m, 2H); rotationalisomer mixture.

1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-(2-hydroxyethyl)-N-ethylcyclopropanecarboxamide(“A26”)

LC-MS retention time: 1.54 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.74-7.61 (m, 3H), 7.34 (d,J=7.3, 1H), 7.22 (dt, J=22.2, 7.5, 2H), 7.12 (d, J=7.3, 1H), 4.97 (s,2H), 4.74 (s, 2H), 3.36-3.09 (m, 4H), 1.41-1.29 (m, 3H), 1.19-1.15 (m,2H), 0.95-0.86 (m, 2H), 0.76-0.64 (m, 2H).

[2-Amino-6-[1-(pyrrolidine-1-carbonyl)cyclopropyl]quinazolin-4-yl]isoindolin-2-ylmethanone(“A27”)

LC-MS retention time: 1.68 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.71-7.67 (m, 1H), 7.65 (d,J=8.8, 1H), 7.62 (d, J=1.8, 1H), 7.35 (d, J=7.3, 1H), 7.27-7.16 (m, 2H),7.12 (d, J=7.3, 1H), 4.96 (s, 2H), 4.72 (s, 2H), 3.24-3.00 (m, 4H),1.55-1.49 (m, 4H), 1.37-1.30 (m, 2H), 1.14-1.10 (m, 2H).

1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-(2-dimethylaminoethyl)-N-ethylcyclopropanecarboxamide(“A28”)

LC-MS retention time: 1.31 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.99-7.91 (m, 2H), 7.76 (d,J=8.6, 1H), 7.47 (d, J=7.5, 1H), 7.34 (dt, J=23.5, 7.2, 2H), 7.25 (d,J=7.5, 1H), 5.07 (s, 2H), 4.81 (s, 2H), 3.96 (s, 2H), 3.63 (t, J=6.4,2H), 3.48 (q, J=7.0, 2H), 3.25 (t, J=6.5, 2H), 2.82 (s, 6H), 1.52 (dd,J=7.0, 4.0, 2H), 1.20 (dd, J=7.0, 4.0, 2H), 1.18 (t, J=7.1, 3H);rotational isomer mixture.

1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-tert-butylcyclobutanecarboxamide(“A29”)

(Preparation by reaction of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclobutanecarboxylicacid [“A61”] with tert-butylamine)

LC-MS retention time: 1.99 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.12 (dd, J=8.9, 2.0, 1H),7.98 (d, J=1.8, 1H), 7.79 (d, J=8.9, 1H), 7.47 (d, J=7.3, 1H), 7.34 (dt,J=19.7, 7.1, 2H), 7.23 (d, J=7.6, 1H), 5.09 (s, 2H), 4.80 (s, 2H),2.79-2.68 (m, 2H), 2.44-2.32 (m, 2H), 1.94-1.72 (m, 2H), 1.14 (s, 9H).

1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethylcyclobutanecarboxamide(“A30”)

LC-MS retention time: 1.73 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.03 (dd, J=8.7, 1.9, 1H),7.91 (d, J=1.8, 1H), 7.76 (d, J=8.8, 1H), 7.48 (d, J=7.5, 1H), 7.34 (dt,J=22.9, 7.2, 2H), 7.25 (d, J=7.3, 1H), 5.07 (s, 2H), 4.81 (s, 2H), 2.99(q, J=7.2, 2H), 2.78-2.70 (m, 2H), 2.43-2.34 (m, 2H), 1.89-1.70 (m, 2H),0.87 (t, J=7.2, 3H).

1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-methylcyclobutanecarboxamide(“A31”)

LC-MS retention time: 1.66 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.00 (dd, J=8.7, 1.9, 1H),7.91 (d, J=1.8, 1H), 7.75 (d, J=8.8, 1H), 7.48 (d, J=7.5, 1H), 7.35 (dt,J=22.0, 7.3, 2H), 7.27 (d, J=7.3, 1H), 5.07 (s, 2H), 4.84 (s, 2H),2.77-2.68 (m, 2H), 2.49 (d, J=6.2, 3H), 2.43-2.33 (m, 2H), 1.91-1.68 (m,2H).

1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-propylcyclobutanecarboxamide(“A32”)

LC-MS retention time: 1.83 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.04 (dd, J=8.8, 2.0, 1H),7.91 (d, J=1.8, 1H), 7.76 (d, J=8.8, 1H), 7.48 (d, J=7.3, 1H), 7.34 (dt,J=23.1, 7.2, 2H), 7.25 (d, J=7.5, 1H), 5.07 (s, 2H), 4.80 (s, 2H), 2.92(t, J=7.1, 2H), 2.78-2.71 (m, 2H), 2.43-2.35 (m, 2H), 1.89-1.70 (m, 2H),1.31-1.22 (m, 2H), 0.65 (t, J=7.3, 3H).

1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-(2-amino-2-oxoethyl)cyclobutanecarboxamide(“A33”)

LC-MS retention time: 1.05 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.04 (dd, J=8.8, 2.0, 1H),7.97 (d, J=1.8, 1H), 7.75 (d, J=8.8, 1H), 7.48 (d, J=7.3, 1H), 7.34 (dt,J=21.5, 7.2, 2H), 7.26 (d, J=7.3, 1H), 5.07 (s, 2H), 4.83 (s, 2H), 3.54(s, 2H), 2.84-2.76 (m, 2H), 2.44-2.36 (m, 2H), 1.95-1.70 (m, 2H).

1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-isobutylcyclobutanecarboxamide(“A34”)

LC-MS retention time: 1.93 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.04 (dd, J=8.7, 1.9, 1H),7.93 (d, J=1.8, 1H), 7.76 (d, J=8.6, 1H), 7.48 (d, J=7.7, 1H), 7.34 (dt,J=23.7, 7.4, 2H), 7.24 (d, J=7.5, 1H), 5.07 (s, 2H), 4.79 (s, 2H),2.83-2.70 (m, 4H), 2.43-2.35 (m, 2H), 1.91-1.69 (m, 2H), 1.60-1.51 (m,1H), 0.64 (d, J=6.8, 6H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-tert-butyl-2-methylpropanamide(“A35”)

(Preparation by reaction of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylpropanoicacid [“A62”] with tert-butylamine);

LC-MS retention time: 1.54 min (“nonpolar” gradient);

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.04 (dd, J=8.9, 2.1, 1H),7.87 (d, J=2.0, 1H), 7.78 (d, J=8.9, 1H), 7.46 (d, J=7.3, 1H), 7.34 (dt,J=18.0, 7.2, 2H), 7.25 (d, J=7.2, 1H), 5.06 (s, 2H), 4.84 (s, 2H), 1.50(s, 6H), 1.19 (s, 9H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethyl-2-methylpropanamide(“A36”)

LC-MS retention time: 1.19 min (“nonpolar” gradient);

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.02 (dd, J=8.9, 2.1, 1H),7.85 (d, J=2.0, 1H), 7.75 (d, J=8.9, 1H), 7.48 (d, J=7.2, 1H), 7.40-7.29(m, 2H), 7.26 (d, J=7.3, 1H), 5.05 (s, 2H), 4.82 (s, 2H), 3.02 (q,J=7.2, 2H), 1.49 (s, 6H), 0.90 (t, J=7.2, 3H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-isobutyl-2-methylpropanamide(“A37”)

LC-MS retention time: 1.47 min (“nonpolar” gradient);

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.02 (dd, J=8.9, 2.1, 1H),7.85 (d, J=2.0, 1H), 7.75 (d, J=8.9, 1H), 7.48 (d, J=7.2, 1H), 7.40-7.29(m, 2H), 7.26 (d, J=7.3, 1H), 5.05 (s, 2H), 4.82 (s, 2H), 3.02 (q,J=7.2, 2H), 1.49 (s, 6H), 0.90 (t, J=7.2, 3H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-propyl-2-methylpropanamide(“A38”)

LC-MS retention time: 1.33 min (“nonpolar” gradient);

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.02 (dd, J=8.9, 2.1, 1H),7.85 (d, J=2.0, 1H), 7.75 (d, J=8.8, 1H), 7.48 (d, J=7.5, 1H), 7.34 (dt,J=21.5, 7.2, 2H), 7.26 (d, J=7.3, 1H), 5.05 (s, 2H), 4.81 (s, 2H), 2.95(t, J=7.1, 2H), 1.50 (s, 6H), 1.38-1.27 (m, 2H), 0.69 (t, J=7.4, 3H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-(2-amino-2-oxoethyl)-2-methylpropanamide(“A39”)

LC-MS retention time: 1.48 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.09 (dd, J=9.0, 2.0, 1H),7.97 (d, J=2.0, 1H), 7.74 (d, J=8.8, 1H), 7.48 (d, J=7.3, 1H), 7.34 (dt,J=21.8, 7.1, 2H), 7.26 (d, J=7.3, 1H), 5.07 (s, 2H), 4.84 (s, 2H), 3.59(s, 2H), 1.54 (s, 6H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-(2-cyanoethyl)-2-methylpropanamide(“A40”)

LC-MS retention time: 1.64 min:

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.02 (dd, J=8.9, 2.1, 1H),7.91 (d, J=2.0, 1H), 7.74 (d, J=9.0, 1H), 7.48 (d, J=7.3, 1H), 7.34 (dt,J=21.1, 7.4, 2H), 7.26 (d, J=7.5, 1H), 5.06 (s, 2H), 4.85 (s, 2H), 3.25(t, J=6.5, 2H), 2.59 (t, J=6.5, 2H), 1.52 (s, 6H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-methyl-5,5-difluoropentanamide(“A41”)

(Preparation by reaction of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-5,5-difluoropentanoicacid [“A63”] with methylamine);

LC-MS retention time: 1.26 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.08-8.03 (m, 1H), 7.93 (d,J=1.7, 1H), 7.72 (d, J=8.8, 1H), 7.43 (d, J=7.5, 1H), 7.30 (dt, J=22.6,7.1, 2H), 7.21 (d, J=7.5, 1H), 5.95 (tt, J=56.9, 4.0, 1H), 5.03 (s, 2H),4.79 (s, 2H), 3.63 (dd, J=8.9, 5.8, 1H), 2.08 (dd, J=19.1, 8.4, 1H),1.81-1.53 (m, 3H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethyl-5,5-difluoropentanamide(“A42”)

LC-MS retention time: 1.76 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.06 (t, J=5.4, 1H), 7.75 (dd,J=8.9, 1.9, 1H), 7.63 (d, J=1.8, 1H), 7.49 (d, J=9.0, 1H), 7.38-7.27 (m,2H), 7.26 (d, J=7.7, 1H), 7.01 (s, 2H), 6.18-5.89 (m, 1H), 5.00 (s, 2H),4.67 (s, 2H), 3.51 (dd, J=8.9, 5.4, 1H), 3.10-2.89 (m, 2H), 2.14-1.53(m, 4H), 0.90 (t, J=7.2, 3H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethylpentanamide(“A43”)

(Preparation by reaction of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]pentanoic acid[“A64”] with ethylamine);

LC-MS retention time: 1.77 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.03 (t, J=5.5, 1H), 7.76 (dd,J=8.9, 1.9, 1H), 7.59 (d, J=1.8, 1H), 7.46 (d, J=8.9, 1H), 7.35-7.24 (m,3H), 7.00 (s, 2H), 4.99 (s, 2H), 4.66 (s, 2H), 3.46 (dd, J=9.5, 5.8,1H), 3.08-2.87 (m, 2H), 1.98-1.46 (m, 2H), 1.26-1.07 (m, 2H), 0.89 (t,J=7.2, 3H), 0.83 (t, J=7.3, 3H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethylhexanamide(“A44”)

(Preparation by reaction of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]hexanoic acid[“A65”] with ethylamine)

LC-MS retention time: 1.89 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.07 (dd, J=8.6, 1.8, 1H),7.89 (d, J=1.7, 1H), 7.71 (d, J=8.8, 1H), 7.46 (d, J=7.5, 1H), 7.31 (dt,J=23.9, 7.3, 2H), 7.22 (d, J=7.5, 1H), 5.03 (s, 2H), 4.78 (s, 2H), 3.55(dd, J=8.7, 6.5, 1H), 3.07-2.85 (m, 2H), 2.00-1.50 (m, 2H), 1.28-1.19(m, 2H), 1.19-1.04 (m, 2H), 0.89 (t, J=7.2, 3H), 0.78 (t, J=7.2, 3H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethyl-5-methyl-hexanamide(“A45”)

(Preparation by reaction of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-5-methylhexanoicacid [“A70”] with ethylamine);

LC-MS retention time: 2.04 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.11 (dd, J=8.8, 1.8, 1H),7.92 (d, J=1.7, 1H), 7.75 (d, J=8.8, 1H), 7.49 (d, J=7.5, 1H), 7.34 (dt,J=24.2, 7.2, 2H), 7.25 (d, J=7.5, 1H), 5.07 (s, 2H), 4.81 (s, 2H), 3.55(dd, J=8.4, 6.8, 1H), 3.10-2.92 (m, 2H), 2.03-1.89 (m, 1H), 1.69-1.57(m, 1H), 1.55-1.43 (m, 1H), 1.16-0.96 (m, 2H), 0.93 (t, J=7.2, 3H), 0.80(dd, J=6.7, 2.3, 6H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethyl-4-methylpentanamide(“A46”)

(Preparation by reaction of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-4-methylpentanoicacid [“A71”] with ethylamine);

LC-MS retention time: 1.92 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.07 (dd, J=8.8, 1.8, 1H),7.90 (d, J=1.8, 1H), 7.71 (d, J=8.6, 1H), 7.45 (d, J=7.5, 1H), 7.31 (dt,J=23.5, 7.2, 2H), 7.21 (d, J=7.5, 1H), 5.04 (s, 2H), 4.78 (s, 2H), 3.69(dd, J=8.8, 6.6, 1H), 3.02 (dq, J=14.5, 7.2, 1H), 2.91 (dq, J=14.3, 7.2,1H), 1.88 (ddd, J=13.2, 8.8, 6.4, 1H), 1.46 (dt, J=13.4, 6.9, 1H), 1.36(td, J=13.2, 6.6, 1H), 0.88 (t, J=7.2, 3H), 0.82 (dd, J=14.0, 6.6, 6H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethyl-3-methylpentanamide(“A47”)

(Preparation by reaction of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-3-methylpentanoicacid [“A72”] with ethylamine);

LC-MS retention time: 1.24 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.14-8.09 (m, 1H), 7.91 (d,J=1.5, 1H), 7.75 (d, J=8.8, 1H), 7.49 (d, J=7.5, 1H), 7.35 (dt, J=24.6,7.3, 2H), 7.25 (d, J=7.5, 1H), 5.06 (s, 2H), 4.81 (s, 2H), 3.29 (dd,J=10.8, 6.2, 1H), 3.06 (ddd, J=14.5, 9.6, 6.1, 1H), 2.90 (dq, J=14.5,7.2, 1H), 2.18-2.04 (m, 1H), 1.49 (ddd, J=13.4, 7.7, 3.3, 1H), 1.20-1.02(m, 1H), 0.96-0.82 (m, 6H), 0.69 (t, J=7.4, 1H), 0.58 (d, J=6.8, 2H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethyl-3-methyl-butanamide(“A48”)

(Preparation by reaction of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-3-methylbutanoicacid [“A73”] with ethylamine);

LC-MS retention time: 1.80 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.07 (dd, J=8.8, 1.8, 1H),7.89 (d, J=1.7, 1H), 7.70 (d, J=8.7, 1H), 7.42 (d, J=7.5, 1H), 7.28 (dt,J=20.1, 7.4, 2H), 7.18 (d, J=7.5, 1H), 5.02 (s, 2H), 4.77 (s, 2H), 3.13(d, J=10.7, 1H), 3.09-2.80 (m, 2H), 2.31-2.16 (m, 1H), 0.95-0.85 (m,6H), 0.62-0.51 (m, 3H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethyl-4-(4-methylpiperazin-1-yl)-4-oxobutanamide(“A49”)

(Preparation by reaction of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-4-(4-methylpiperazin-1-yl)-4-oxobutanoicacid [“A75”] with ethylamine);

LC-MS retention time: 1.24 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.09 (d, J=8.8, 1H), 8.00 (s,1H), 7.76 (d, J=8.8, 1H), 7.49 (d, J=7.5, 1H), 7.38 (t, J=7.4, 1H), 7.33(t, J=7.4, 1H), 7.26 (s, 1H), 5.10 (s, 2H), 4.81 (s, 2H), 4.42 (s, 1H),4.18 (s, 2H), 3.52-2.62 (m, 13H), 0.89 (t, J=7.2, 3H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N′-ethyl-2-methylene-pentanediamide(“A50”)

(Preparation by reaction of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-4-carbamoylpent-4-enoicacid [“A74”] with ethylamine);

LC-MS retention time: 1.66 min.

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-(3,3-difluoropropyl)-N-ethyl-5,5-difluoropentanamide(“A51”)

(Preparation by reaction of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-(3,3-difluoropropyl)-5,5-difluoropentanoicacid [“A66”] with ethylamine);

LC-MS retention time: 1.99 min.

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-(3,3-difluoropropyl)-5,5-difluoro-N-(1,1,3,3-tetramethylbutyl)pentanamide(“A52”)

LC-MS retention time: 2.25 min (“nonpolar” gradient).

1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethylcyclopentanecarboxamide(“A53”)

(Preparation by reaction of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclopentanecarboxylicacid [“A68”] with ethylamine);

LC-MS retention time: 1.84 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.74 (dd, J=9.1, 2.1, 1H),7.70 (t, J=5.6, 1H), 7.61 (d, J=2.0, 1H), 7.45 (d, J=7.5, 1H), 7.33 (t,J=7.4, 1H), 7.28 (t, J=7.2, 1H), 7.25 (d, J=7.3, 1H), 4.99 (s, 2H), 4.66(s, 2H), 3.74 (d, J=11.7, 2H), 3.46-3.38 (m, 2H), 3.03-2.95 (m, 2H),2.42-2.34 (m, 2H), 1.85-1.75 (m, 2H), 0.86 (t, J=7.2, 3H).

1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethyltetrahydropyran-4-carboxamide(“A54”)

(Preparation by reaction of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]tetrahydropyran-4-carboxylicacid [“A69”] with ethylamine);

LC-MS retention time: 1.59 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.74 (dd, J=9.1, 2.1, 1H),7.70 (t, J=5.6, 1H), 7.61 (d, J=2.0, 1H), 7.45 (d, J=7.5, 1H), 7.33 (t,J=7.4, 1H), 7.28 (t, J=7.2, 1H), 7.25 (d, J=7.3, 1H), 4.99 (s, 2H), 4.66(s, 2H), 3.74 (d, J=11.7, 2H), 3.46-3.38 (m, 2H), 3.03-2.95 (m, 2H),2.42-2.34 (m, 2H), 1.85-1.75 (m, 2H), 0.86 (t, J=7.2, 3H).

2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethyl-2-methylpentanamide(“A55”)

(Preparation by reaction of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl-2-methylpentanoicacid [“A67”] with ethylamine);

LC-MS retention time: 1.48 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.90 (dd, J=9.0, 2.0, 1H),7.76 (d, J=1.8, 1H), 7.65 (d, J=8.8, 1H), 7.35 (d, J=7.5, 1H), 7.22 (dt,J=22.4, 7.2, 2H), 7.13 (d, J=7.3, 1H), 4.96 (s, 2H), 4.73 (s, 2H),3.02-2.87 (m, 2H), 1.87 (td, J=13.1, 4.7, 1H), 1.78-1.68 (m, 1H), 1.37(s, 3H), 1.13-0.95 (m, 2H), 0.81 (t, J=7.2, 3H), 0.75 (t, J=7.2, 3H).

EXAMPLE 7 Preparation of ethyl1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-cyclopropanecarboxylate(“A56”) and1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclopropanecarboxylicacid (“A57”) Step 1: Ethyl 1-(4-nitrophenyl)cyclopropanecarboxylate

20 g of ethyl 4-nitrophenylacetate are dissolved in 30 ml of DMF andadded dropwise to a suspension of 4 g of sodium hydride in 20 ml of DMFwith ice-cooling. 8.5 ml of dibromoethane are subsequently added, andthe mixture is stirred at 55° C. for 1 h. A further 5 g of sodiumhydride and 8.5 ml of dibromoethane are added with ice-cooling, and themixture is then stirred at 50° C. for 2 h. After cooling, the reactionmixture is stirred into a mixture of 100 ml of 1 N hydrochloric acid and200 g of ice. The mixture is washed four times with 100 ml of diethylether each time, the combined organic phases once with 100 ml of sodiumchloride solution, dried over sodium sulfate and, after filtration,evaporated to dryness in vacuo. The residue is purified by columnchromatography (reversed phase). Yield: 8.5 g (38%) of ethyl1-(4-nitrophenyl)cyclopropanecarboxylate; LC-MS retention time: 2.01 min(“nonpolar” gradient);

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.14 (d, J=8.9, 2H), 7.60 (d,J=8.9, 2H), 4.03 (q, J=7.0, 2H), 1.56 (q, J=4.1, 2H), 1.26 (q, J=4.3,2H), 1.08 (t, J=7.0, 3H).

Step 2: Ethyl 1-(4-aminophenyl)cyclopropanecarboxylate

11.3 g of ethyl 1-(4-nitrophenyl)cyclopropanecarboxylate are dissolvedin 110 ml of tetrahydrofuran, 1 g of 5% Pd/C (52.3% of water) is added,and the mixture is stirred at 23° C. under a hydrogen atmosphere for 1h. After aeration, the solid material is filtered off, and the filtrateis evaporated to dryness in vacuo. Yield: 9.8 g (100%) of ethyl1-(4-aminophenyl)cyclopropanecarboxylate; LC-MS retention time: 1.18 min(“nonpolar” gradient).

Step 3: Ethyl2-[4-[[(2Z/E)-2-hydroxyiminoacetyl]amino]phenylcyclopropanecarboxylate

9 g of chloral hydrate are dissolved in 50 ml of water, 14 g of Na₂SO₄are added, and the mixture is stirred at 23° C. for 10 min. A solutionof 10 g of ethyl 1-(4-aminophenyl)cyclopropanecarboxylate hydrochloridein 50 ml of water is added to this solution. 10 g of hydroxylammoniumchloride in 20 ml of water are added to the resultant suspension, andthe mixture is stirred at 60° C. for 90 min. The mixture is subsequentlyallowed to cool, during which a precipitate deposits. This is filteredoff, washed with water and dried at 40° C. in vacuo. The mixtureobtained is employed in the following reaction without furtherpurification.

Yield: 12.5 g (95%) of ethyl2-[4-[[(2Z/E)-2-hydroxyiminoacetyl]amino]-phenylcyclopropanecarboxylate;

LC-MS retention time: 1.48 min.

Step 4: 1-(2,3-Dioxoindolin-5-yl))cyclopropanoic acid

12.5 g of ethyl2-[4-[[(2Z/E)-2-hydroxyiminoacetyl]amino]phenylcyclopropanecarboxylateare added in portions to 30 ml of sulfuric acid (98%) at 50° C., duringwhich the temperature rises to 60° C. When the addition is complete, themixture is stirred for a further 30 min and subsequently poured into 400ml of ice-water. The resultant precipitate is filtered off and washedwith water. Drying at 40° C. in vacuo gives 6.5 g (62%) of(2,3-dioxo-2,3-dihydro-1H-indol-5-yl)cyclopropanecarboxylic acid;

LC-MS retention time: 1.40 min.

Step 5: Ethyl 1-(2,3-dioxoindolin-5-yl)cyclopropanoate

6.5 g of (2,3-dioxo-2,3-dihydro-1H-indol-5-yl)cyclopropanecarboxylicacid are dissolved in 100 ml of ethanol, and 500 mg oftoluene-4-sulfonic acid monohydrate are added. The mixture is heated at80° C. for 1 h and subsequently evaporated in vacuo. The residue istaken up in 100 ml of water and 100 ml of ethyl acetate and stirred at60° C. for a further 12 h. The mixture is neutralised using sodiumhydrogencarbonate, and the organic phase is separated off. The aqueousphase is washed a further twice with 100 ml of ethyl acetate each time.The combined organic phases are dried over sodium sulfate, filtered andevaporated to dryness in vacuo, giving 6.7 g (92%) of ethyl1-(2,3-dioxoindolin-5-yl)cyclopropanecarboxylate; LC-MS retention time:1.30 min.

Step 6:5-(1-Ethoxycarbonylcyclopropyl)-1-tert-butoxycarbonyl-2,3-dioxoindoline

6 g of di-tert-butyl dicarbonate are added to 6.7 g of ethyl1-(2,3-dioxoindolin-5-yl))cyclopropanecarboxylate and 15 mg of4-dimethylaminopyridine in 100 ml of tetrahydrofuran, and the mixture issubsequently stirred at 23° C. for 12 h. The mixture is evaporated at23° C. in vacuo and processed further directly. Yield: 9.3 g (100%) of5-(1-ethoxycarbonylcyclopropyl)-1-tert-butoxycarbonyl-2,3-dioxoindoline;

LC-MS retention time: 2.20 min (“nonpolar” gradient).

Step 7: Ethyl1-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]cyclopropanecarboxylate

3.2 g of isoindoline are added to 9.3 g of5-(1-ethoxycarbonylcyclopropyl)-1-tert-butoxycarbonyl-2,3-dioxoindolinein 100 ml of tetrahydrofuran, and the mixture is subsequently stirred at23° C. for 1 h. The mixture is evaporated to dryness in vacuo andpurified by column chromatography, giving 4.0 g (32%) of ethyl1-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]cyclopropanecarboxylate;

LC-MS retention time: 2.63 min (“nonpolar” gradient).

Step 8: Ethyl1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclopropanecarboxylate(“A56”)

670 mg of ethyl1-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]cyclopropanecarboxylateare dissolved in 15 ml of acetonitrile under argon. 213 mg of caesiumfluoride and 380 μl of bis(trimethylsilyl)carbodiimide are added to thesolution. The mixture is stirred at room temperature for 15 min, and 2.7ml of hydrochloric acid (1N) are then added, with the productprecipitating as white solid. Yield: 510 mg (91%) of ethyl1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclopropanecarboxylate;LC-MS retention time: 1.65 min (“nonpolar” gradient);

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.07 (dd, J=8.7, 1.9, 1H),8.00 (d, J=1.8, 1H), 7.75 (d, J=8.6, 1H), 7.46 (d, J=7.3, 1H), 7.34 (dt,J=22.6, 7.2, 2H), 7.25 (d, J=7.3, 1H), 5.07 (s, 2H), 4.84 (s, 2H), 4.03(q, J=7.1, 2H), 1.59 (q, J=4.0, 2H), 1.28 (q, J=4.2, 2H), 1.08 (t,J=7.1, 3H).

Step 9:1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclopropanecarboxylicacid (“A57”)

400 mg of ethyl1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclopropanecarboxylateare dissolved in 14 ml of tetrahydrofuran, and 3.5 ml of 2N sodiumhydroxide solution are added. The mixture is stirred at 23° C. for 12 h,evaporated to dryness in vacuo, taken up in 10 ml of water and adjustedto pH 2 using 1 ml of 25% hydrochloric acid. The resultant precipitateis filtered off and dried in vacuo. Yield: 250 mg (67%) of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclopropanecarboxylicacid;

LC-MS retention time: 1.63 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.05 (dd, J=8.6, 1.8, 1H),7.94 (d, J=1.8, 1H), 7.70 (d, J=8.6, 1H), 7.44 (d, J=7.5, 1H), 7.31 (dt,J=22.0, 7.2, 2H), 7.23 (d, J=7.3, 1H), 5.03 (s, 2H), 4.80 (s, 2H), 1.52(dd, J=7.0, 4.0, 2H), 1.20 (dd, J=7.0, 4.0, 2H).

EXAMPLE 8 Preparation of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-cyclobutanecarboxylicacid (“A61”)

Step 1: Ethyl 1-(4-nitrophenyl)cyclobutanecarboxylate

10 g of ethyl 4-nitrophenylacetate are dissolved in 100 ml of DMF, addeddropwise to a suspension of 4.97 g of sodium hydride in 20 ml of DMFwith ice-cooling and stirred for 30 min. 6.6 ml of 1,3-dibromopropaneare subsequently added, and the mixture is stirred at 23° C. for 12 h.The reaction mixture is subsequently stirred into a mixture of 100 ml of1 N hydrochloric acid and 200 g of ice. The mixture is washed four timeswith 100 ml of ethyl acetate each time, the combined organic phases oncewith 100 ml of sodium chloride solution, dried over sodium sulfate and,after filtration, evaporated to dryness in vacuo. The residue ispurified by column chromatography (reversed phase). Yield: 5.5 g (46%)of ethyl 1-(4-nitrophenyl)cyclobutanecarboxylate; LC-MS retention time:2.21 min (“nonpolar” gradient);

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.22 (d, J=8.9, 2H), 7.55 (d,J=8.9, 2H), 4.09 (q, J=7.1, 2H), 2.86-2.76 (m, 2H), 2.58-2.47 (m, 2H),2.11-1.99 (m, 1H), 1.93-1.80 (m, 1H), 1.13 (t, J=7.1, 3H).

Step 2: Ethyl 1-(4-aminophenyl)cyclobutanecarboxylate

5.5 g of ethyl 1-(4-nitrophenyl)cyclobutanecarboxylate are dissolved in55 ml of tetrahydrofuran, 2 g of 5% Pd/C (52.3% of water) are added, andthe mixture is stirred at 23° C. under a hydrogen atmosphere for 1 h.After aeration, insoluble material is filtered off, and the filtrate isevaporated to dryness in vacuo. Yield: 4.3 g (89%) of ethyl1-(4-aminophenyl)cyclobutanecarboxylate; LC-MS retention time: 2.05 min(“nonpolar” gradient).

Step 3: Ethyl2-[4-[[(2Z/E)-2-hydroxyiminoacetyl]amino]phenylcyclobutanecarboxylate

6.25 g of chloral hydrate are dissolved in 180 ml of water, 9.39 g ofNa₂SO₄ are added, and the mixture is stirred at 23° C. for 10 min. Asolution of 6.9 g of ethyl 1-(4-aminophenyl)cyclobutanecarboxylatehydrochloride in 50 ml of water is added to this solution. 7.65 g ofhydroxylammonium chloride in 20 ml of water are added to the resultantsuspension, and the mixture is stirred at 60° C. for 5 h. The mixture issubsequently allowed to cool, during which an oil deposits. This mixtureis washed three times with 50 ml of dichloromethane each time, thecombined organic phases are dried over sodium sulfate, filtered off andevaporated to dryness in vacuo. The mixture obtained is employed in thefollowing reaction without further purification:

Yield: 9.1 g (100%) of ethyl2-[4-[[(2Z/E)-2-hydroxyiminoacetyl]amino]phenyl-cyclobutanecarboxylate;LC-MS retention time: 2.02 min.

Step 4: 1-(2,3-Dioxoindolin-5-yl))cyclobutanoic acid

8.0 g of ethyl2-[4-[[(2Z/E)-2-hydroxyiminoacetyl]amino]phenyl-cyclobutanecarboxylateare added in portions to 30 ml of sulfuric acid (98%) at 50° C., duringwhich the temperature rises to 60° C. When the addition is complete, themixture is stirred at 50° C. for a further 120 min and subsequentlypoured into 400 ml of ice-water. The mixture is washed three times with200 ml of dichloromethane/ethanol (9:1) each time, the combined organicphases are dried over sodium sulfate, filtered off and evaporated todryness in vacuo. The crude product obtained is employed in the nextreaction without further purification.

Yield: 7.2 g (100%) of 1-(2,3-dioxoindolin-5-yl)cyclobutanoic acid;

LC-MS retention time: 1.51 min.

Step 5: Ethyl 1-(2,3-dioxoindolin-5-yl))cyclobutanecarboxylate

7.2 g of 1-(2,3-dioxoindolin-5-yl)cyclobutanecarboxylic acid aredissolved in 100 ml of ethanol, and 500 mg of toluene-4-sulfonic acidmonohydrate are added. The mixture is heated at 80° C. for 1 h andsubsequently evaporated in vacuo. The residue is taken up in 100 ml ofwater and 100 ml of ethyl acetate, and the aqueous phase is separatedoff. The aqueous phase is washed a further twice with 100 ml of ethylacetate each time. The combined organic phases are dried over sodiumsulfate, filtered and evaporated to dryness in vacuo. The residue ispurified by column chromatography (reversed phase), giving 2.4 g (30%)of ethyl 1-(2,3-dioxoindolin-5-yl)cyclobutanecarboxylate;

LC-MS retention time: 1.99 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.50 (dd, J=8.2, 2.0, 1H),7.39 (d, J=2.0, 1H), 6.94 (d, J=8.1, 1H), 4.07 (m, 2H), 2.79-2.69 (m,2H), 2.42 (m, 2H), 2.03-1.77 (m, 2H), 1.22-1.11 (m, 3H).

Step 6:5-(1-Ethoxycarbonylcyclobutyl)-1-tert-butoxycarbonyl-2,3-dioxoindoline

2.2 g of di-tert-butyl dicarbonate are added to 2.4 g of ethyl1-(2,3-dioxoindolin-5-yl))cyclobutanoate and 5 mg of4-dimethylaminopyridine in 50 ml of tetrahydrofuran, and the mixture issubsequently stirred at 23° C. for 12 h. The mixture is evaporated at23° C. in vacuo and processed further directly. Yield: 3.3 g (100%) of5-(1-ethoxycarbonylcyclobutyl)-1-tert-butoxycarbonyl-2,3-dioxoindoline;LC-MS retention time: 2.35 min (“nonpolar” gradient).

Step 7: Ethyl 1-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]cyclobutanecarboxylate

1.049 g of isoindoline are added to 3.3 g of5-(1-ethoxycarbonylcyclobutyl)-1-tert-butoxycarbonyl-2,3-dioxoindolinein 50 ml of tetrahydrofuran, and the mixture is subsequently stirred at23° C. for 1 h. The mixture is evaporated to dryness in vacuo andpurified by column chromatography, giving 1.2 g (28%) of ethyl1-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]cyclobutanecarboxylate;LC-MS retention time: 2.75 min (“nonpolar” gradient).

Step 8: Ethyl1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclobutanecarboxylate

1.2 g of ethyl1-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]cyclobutanecarboxylateare dissolved in 50 ml of acetonitrile under argon. 370 mg of caesiumfluoride and 679 μl of bis(trimethylsilyl)carbodiimide are added to thesolution. The mixture is stirred at room temperature for 15 min, and 6ml of hydrochloric acid (1N) are then added, and the mixture isneutralised using bicarbonate. The aqueous phase is washed 3 times with100 ml of ethyl acetate each time. The combined organic phases are driedover sodium sulfate, filtered and evaporated to dryness in vacuo. Yield:1 g (99%) of ethyl1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclobutanecarboxylate(oil);

LC-MS retention time: 1.75 min (“nonpolar” gradient).

Step 9:1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclobutanecarboxylicacid

1.0 g of ethyl1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclobutanecarboxylateare dissolved in 15 ml of tetrahydrofuran, and 10 ml of 2N sodiumhydroxide solution are added. The mixture is stirred at 50° C. for 4 hand subsequently evaporated in vacuo. The mixture is then adjusted topH2 using 3 ml of 25% hydrochloric acid with ice-cooling, with yellowcrystals precipitating. The precipitate obtained is filtered off anddried in vacuo. Yield: 800 mg (86%) of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclobutanecarboxylicacid; LC-MS retention time: 1.32 min.

EXAMPLE 9 Preparation of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylpropanoicacid (“A62”)

Step 1: Ethyl 2-methyl-2-(4-nitrophenyl)propanoate

10 g of ethyl 4-nitrophenylacetate are dissolved in 100 ml of DMF, addeddropwise to a suspension of 4.97 g of sodium hydride in 20 ml of DMFwith ice-cooling and stirred for 30 min. 7.14 ml of methyl iodide aresubsequently added, and the mixture is stirred at 23° C. for 12 h. Thereaction mixture is subsequently stirred into 100 ml of saturatedammonium chloride solution. The mixture is washed four times with 100 mlof ethyl acetate each time, the combined organic phases with 100 ml ofsodium chloride solution, dried over sodium sulfate and, afterfiltration, evaporated to dryness in vacuo. The residue is purified bycolumn chromatography (reversed phase). Yield: 8.2 g (72%) of ethyl2-methyl-2-(4-nitrophenyl)propanoate; LC-MS retention time: 2.39 min.

Step 2: Ethyl 2-(4-aminophenyl)-2-methylpropanoate

8.7 g of ethyl 2-methyl-2-(4-nitrophenyl)propanoate are dissolved in 90ml of tetrahydrofuran, 2 g of 5% Pd/C (52.3% of water) are added, andthe mixture is stirred at 23° C. under a hydrogen atmosphere for 1 h.After aeration, the solid material is filtered off, and the filtrate isevaporated to dryness in vacuo.

Yield: 7.3 g (97%) of ethyl 2-(4-aminophenyl)-2-methylpropanoate; LC-MSretention time: 2.39 min.

Step 3: Ethyl2-[4-[[(2E)-2-hydroxyiminoacetyl]amino]phenyl]-2-methylpropanoate

7.23 g of chloral hydrate are dissolved in 180 ml of water, 10.87 g ofNa₂SO₄ are added, and the mixture is stirred at 23° C. for 10 min. Asolution of 7.55 g of ethyl 2-(4-aminophenyl)-2-methylpropanoatehydrochloride in 50 ml of water is added to this solution. 8.86 g ofhydroxylammonium chloride in 20 ml of water are added to the resultantsuspension, and the mixture is stirred at 60° C. for 5 h. The mixture issubsequently allowed to cool, during which an orange oil deposits. Thismixture is washed three times with 50 ml of dichloromethane each time,the combined organic phases are dried over sodium sulfate, filtered offand evaporated to dryness in vacuo. The mixture obtained is employed inthe following reaction without further purification.

Yield: 10.0 g (98%) of ethyl2-[4-[[(2E)-2-hydroxyiminoacetyl]amino]phenyl]-2-methylpropanoate; LC-MSretention time: 1.92 min.

Step 4: Ethyl 2-(2,3-dioxoindolin-5-yl)-2-methylpropanoate

8.0 g of ethyl2-[4-[[(2E)-2-hydroxyiminoacetyl]amino]phenyl]-2-methylpropanoate areadded in portions to 30 ml of sulfuric acid (98%) at 50° C., duringwhich the temperature rises to 60° C. When the addition is complete, themixture is stirred at 50° C. for a further 120 min and subsequentlypoured into 400 ml of ice-water. The mixture is washed three times with200 ml of dichloromethane/ethanol (9:1) each time, the combined organicphases are dried over sodium sulfate, filtered off and evaporated todryness in vacuo. The crude product obtained is employed in the nextreaction without further purification. Yield: 7.2 g (100%) of ethyl2-(2,3-dioxoindolin-5-yl)-2-methyl propanoate obtained; LC-MS retentiontime: 1.80 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.56 (dd, J=8.4, 2.1, 1H),7.45 (d, J=1.8, 1H), 6.92 (d, J=8.2, 1H), 4.08 (q, J=7.0, 2H), 1.51 (s,6H), 1.14 (t, J=7.1, 3H).

Step 5:5-(2-Ethoxy-1,1-dimethyl-2-oxoethyl))-1-tert-butoxycarbonyl-2,3-dioxoindoline

2.51 g of di-tert-butyl dicarbonate are added to 3.0 g of ethyl2-(2,3-dioxoindolin-5-yl)-2-methylpropanoate and 50 mg of4-dimethylaminopyridine in 50 ml of tetrahydrofuran, and the mixture issubsequently stirred at 23° C. for 12 h. The mixture is evaporated at23° C. in vacuo and processed further directly. Yield: 4.1 g (99%) of5-(2-ethoxy-1,1-dimethyl-2-oxoethyl))-1-tertbutoxycarbonyl-2,3-dioxoindoline;LC-MS retention time: 2.25 min (“nonpolar” gradient).

Step 6: Ethyl2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]-2-methylpropanoate

1.368 g of isoindoline are added to 4.15 g of5-(2-ethoxy-1,1-dimethyl-2-oxoethyl))-1-tert-butoxycarbonyl-2,3-dioxoindolinein 50 ml of tetrahydrofuran, and the mixture is subsequently stirred at23° C. for 1 h. The mixture is evaporated to dryness in vacuo andpurified by column chromatography, giving 3.2 g (58%) of ethyl2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]-2-methylpropanoate;LC-MS retention time: 2.68 min (“nonpolar” gradient).

Step 7: Ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylpropanoate

3.2 g of ethyl2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]-2-methylpropanoateare dissolved in 100 ml of acetonitrile under argon. 1.012 g of caesiumfluoride and 1.81 ml of bis(trimethylsilyl)carbodiimide are added to thesolution. The mixture is stirred at room temperature for 15 min, and 14ml of hydrochloric acid (1N) are then added, and the mixture isneutralised using bicarbonate. The aqueous phase is washed three timeswith 100 ml of ethyl acetate each time. The combined organic phases aredried over sodium sulfate, filtered and evaporated to dryness in vacuo.

Yield: 2.4 g (89%) of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylpropanoate(oil);

LC-MS retention time: 2.29 min (“nonpolar” gradient).

Step 8:2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylpropanoicacid

2.4 g of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylpropanoateare dissolved in 40 ml of tetrahydrofuran, and 25 ml of 2N sodiumhydroxide solution are added. The mixture is stirred at 50° C. for 4 hand subsequently evaporated in vacuo. The mixture is then adjusted topH2 using 7 ml of 25% hydrochloric acid with ice-cooling, with yellowcrystals precipitating. The precipitate obtained is filtered off anddried in vacuo. Yield: 2.0 g (90%) of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylpropanoicacid;

LC-MS retention time: 1.23 min (“nonpolar” gradient).

EXAMPLE 10 Preparation of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-5,5-difluoropentanoicacid (“A63”)

Step 1: Ethyl 2-(4-aminophenyl)-5,5-difluoropent-4-enoate and ethyl4-aminophenyl)-2-(3,3-difluoroallyl)-5,5-difluoropent-4-enoate

7.113 g of ethyl 4-nitrophenylacetate are dissolved in 60 ml of DMF,added dropwise to a suspension of 3.4 g of sodium hydride in 40 ml ofDMF with ice-cooling and stirred for 30 min. 8.8 g of1,3-dibromo-1,1,-difluoropropane are subsequently added, and the mixtureis stirred at 23° C. for 12 h. The reaction mixture is subsequentlystirred into 100 ml of saturated ammonium chloride solution. The mixtureis washed four times with 100 ml of ethyl acetate each time, thecombined organic phases with 100 ml of sodium chloride solution, driedover sodium sulfate and, after filtration, evaporated to dryness invacuo. The residue is purified by column chromatography (reversedphase). Yield: 5.4 g (56%) of ethyl2-(4-aminophenyl)-5,5-difluoropent-4-enoate; LC-MS retention time: 2.21min (“nonpolar” gradient);

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.26-8.22 (m, 2H), 7.60-7.53(m, 2H), 4.18 (q, J=7.1, 2H), 2.82-2.68 (m, 3H), 1.99 (s, 1H), 1.17 (t,J=7.1, 3H);

and 2.4 g (25%) of ethyl4-aminophenyl)-2-(3,3-difluoroallyl)-5,5-difluoropent-4-enoate; LC-MSretention time: 2.49 min (“nonpolar” gradient);

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.25-8.19 (m, 2H), 7.63-7.57(m, 2H), 4.04 (q, J=7.2, 2H), 2.74-2.64 (m, 1H), 2.51 (dt, J=3.7, 1.8,2H), 2.49-2.39 (m, 1H), 1.18 (t, J=7.2, 2H), 1.14 (t, J=7.1, 3H).

Step 2: Ethyl 2-(4-aminophenyl-5,5-difluoropentanoate

5.4 g of ethyl 2-(4-aminophenyl)-5,5-difluoropent-4-enoate are dissolvedin 60 ml of tetrahydrofuran, 2 g of 5% Pd/C (52.3% of water) are added,and the mixture is stirred at 23° C. under a hydrogen atmosphere for 1h. After aeration, the solid material is filtered off, and the filtrateis evaporated to dryness in vacuo. Yield: 5.0 g (99%) of ethyl2-(4-aminophenyl-5,5-difluoropentanoate;

LC-MS retention time: 1.67 min.

Step 3: Ethyl5,5-difluoro-2-[4-[[(2E)-2-hydroxyiminoacetyl]amino]phenyl]-pentanoate

3.804 g of chloral hydrate are dissolved in 40 ml of water, 5.68 g ofNa₂SO₄ are added, and the mixture is stirred at 23° C. for 10 min. Asolution of 5.0 g of ethyl 2-(4-aminophenyl-5,5-difluoropentanoatehydrochloride in 40 ml of water is added to this solution. 4.169 g ofhydroxylammonium chloride in 20 ml of water are added to the resultantsuspension, and the mixture is stirred at 60° C. for 5 h. The mixture issubsequently allowed to cool, during which an orange oil deposits. Thismixture is washed three times with 50 ml of dichloromethane each time,the combined organic phases are dried over sodium sulfate, filtered offand evaporated to dryness in vacuo. The mixture obtained was employed inthe following reaction without further purification. Yield: 5.0 g (78%)of ethyl5,5-difluoro-2-[4-[[(2E)-2-hydroxyiminoacetyl]amino]phenyl]pentanoate;LC-MS retention time: 1.99 min.

Step 4: Ethyl 2-(2,3-dioxoindolin-5-yl)-5,5-difluoropentanoate

6.0 g of ethyl5,5-difluoro-2-[4-[[(2E)-2-hydroxyiminoacetyl]amino]phenyl]-pentanoateare added in portions to 30 ml of sulfuric acid (98%) at 50° C., duringwhich the temperature rises to 60° C. When the addition is complete, themixture is stirred at 50° C. for a further 120 min and subsequentlypoured into 200 ml of ice-water. The mixture is washed three times with200 ml of dichloromethane/ethanol (9:1) each time, the combined organicphases are dried over sodium sulfate, filtered off and evaporated todryness in vacuo. The crude product obtained is employed in the nextreaction without further purification. Yield: 4.2 g (74%) of ethyl2-(2,3-dioxoindolin-5-yl)-5,5-difluoropentanoate;

LC-MS retention time: 1.95 min

Step 5:5-(1-Ethoxycarbonyl-4,4-difluorobutyl)-1-tert-butoxycarbonyl-2,3-dioxoindoline

3.71 g of di-tert-butyl dicarbonate are added to 4.0 g of ethyl2-(2,3-dioxoindolin-5-yl)-5,5-difluoropentanoate and 50 mg of4-dimethylaminopyridine in 50 ml of tetrahydrofuran, and the mixture issubsequently stirred at 23° C. for 12 h. The mixture is evaporated at23° C. in vacuo and processed further directly. Yield: 5.3 g (99%) of5-(1-ethoxycarbonyl-4,4-difluorobutyl)-1-tertbutoxycarbonyl-2,3-dioxoindoline;LC-MS retention time: 2.24 min (“nonpolar” gradient).

Step 6: Ethyl2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]-5,5-difluoropentanoate

1.53 g of isoindoline are added to 5.29 g of5-(1-ethoxycarbonyl-4,4-difluorobutyl)-1-tert-butoxycarbonyl-2,3-dioxoindolinein 50 ml of tetrahydrofuran, and the mixture is subsequently stirred at23° C. for 1 h. The mixture is evaporated to dryness in vacuo andpurified by column chromatography, giving 1.7 g (25%) of ethyl2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]-5,5-difluoropentanoate;LC-MS retention time: 2.62 min (“nonpolar” gradient).

Step 7: Ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-5,5-difluoropentanoate

1.7 g of ethyl2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]-5,5-difluoropentanoateare dissolved in 50 ml of acetonitrile under argon. 486 mg of caesiumfluoride and 869 μl of bis(trimethylsilyl)carbodiimide are added to thesolution. The mixture is stirred at room temperature for 15 min, and 6ml of hydrochloric acid (1N) are then added, and the mixture isneutralised using bicarbonate. The aqueous phase is washed three timeswith 100 ml of ethyl acetate each time. The combined organic phases aredried over sodium sulfate, filtered and evaporated to dryness in vacuo.Yield: 1.4 g (96%) of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-5,5-difluoropentanoate(oil); LC-MS retention time: 1.71 min (“nonpolar” gradient).

Step 8:2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-5,5-difluoropentanoicacid

1.2 g of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-5,5-difluoropentanoateare dissolved in 15 ml of tetrahydrofuran, and 10 ml of 2N sodiumhydroxide solution are added. The mixture is stirred at 50° C. for 4 hand subsequently evaporated in vacuo. The mixture is then adjusted topH2 using 25% hydrochloric acid with ice-cooling, with yellow crystalsprecipitating. The precipitate obtained is filtered off and dried invacuo. Yield: 800 mg (71%) of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-5,5-difluoropentanoicacid; LC-MS retention time: 1.35 min (“nonpolar” gradient).

EXAMPLE 11 Preparation of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]pentanoic acid(“A64”)

Step 1: Ethyl 2-(4-nitrophenyl)pentanoate

6.694 g of ethyl 4-nitrophenylacetate are dissolved in 30 ml of DMF,added dropwise to a suspension of 1.4 g of sodium hydride in 30 ml ofDMF with ice-cooling and stirred for 30 min. 2.91 ml of 1-bromopropanein 20 ml of DMF are subsequently added, and the mixture is stirred at23° C. for 12 h. The reaction mixture is subsequently stirred into 100ml of saturated ammonium chloride solution. The mixture is washed fourtimes with 100 ml of ethyl acetate each time, the combined organicphases with 100 ml of sodium chloride solution, dried over sodiumsulfate and, after filtration, evaporated to dryness in vacuo. Theresidue is purified by column chromatography (reversed phase). Yield:5.3 g (66%) of ethyl 2-(4-nitrophenyl)pentanoate; LC-MS retention time:2.28 min (“nonpolar” gradient).

Step 2: Ethyl 2-(4-aminophenyl)pentanoate

5.3 g of ethyl 2-(4-nitrophenyl)pentanoate are dissolved in 55 ml oftetrahydrofuran, 1 g of 5% Pd/C (52.3% of water) is added, and themixture is stirred at 23° C. under a hydrogen atmosphere for 1 h. Afteraeration, the solid material is filtered off, and the filtrate isevaporated to dryness in vacuo. Yield: 4.7 g (99%) of ethyl2-(4-aminophenyl)pentanoate (oil); LC-MS retention time: 1.40 min(“nonpolar” gradient).

Step 3: Ethyl 2-[4-[[(2Z/E)-2-hydroxyiminoacetyl]amino]phenyl]pentanoate

4.135 g of chloral hydrate are dissolved in 50 ml of water, 6.11 g ofNa₂SO₄ are added, and the mixture is stirred at 23° C. for 10 min. Asolution of 4.7 g of ethyl 2-(4-aminophenyl)pentanoate hydrochloride in50 ml of water is added to this solution. 5.11 g of hydroxylammoniumchloride in 20 ml of water are added to the resultant suspension, andthe mixture is stirred at 60° C. for 5 h. The mixture is subsequentlyallowed to cool, during which an orange oil deposits. This mixture iswashed three times with 50 ml of dichloromethane each time, the combinedorganic phases are dried over sodium sulfate, filtered off andevaporated to dryness in vacuo. The mixture obtained is employed in thefollowing reaction without further purification.

Yield: 5.2 g (78%) of ethyl2-[4-[[(2Z/E)-2-hydroxyiminoacetyl]amino]phenyl]-pentanoate; LC-MSretention time: 1.76 min (“nonpolar” gradient).

Step 4: Ethyl 2-(2,3-dioxoindolin-5-yl)pentanoate

30 ml of sulfuric acid (98%) are added in portions to 6.2 g of ethyl2-[4-[[(2Z/E)-2-hydroxyiminoacetyl]amino]phenyl]pentanoate, during whichthe temperature rises to 60° C. When the addition is complete, themixture is stirred at 50° C. for a further 120 min and subsequentlypoured into 400 ml of ice-water. The mixture is washed three times with200 ml of dichloromethane/ethanol (9:1) each time, the combined organicphases are dried over sodium sulfate, filtered off and evaporated todryness in vacuo. The crude product obtained is employed in the nextreaction without further purification. Yield: 5.3 g (mixture of ethyl2-(2,3-dioxoindolin-5-yl)pentanoate and2-(2,3-dioxoindolin-5-yl)pentanoic acid in the ratio 20:80); LC-MSretention time: 2.08 min (ester) and 1.62 min (acid).

Step 5: Ethyl 2-(2,3-dioxoindolin-5-yl)pentanoate

The resultant mixture of ethyl 2-(2,3-dioxoindolin-5-yl)pentanoate and2-(2,3-dioxoindolin-5-yl)pentanoic acid (5.3 g) from the precedingreaction is dissolved in 100 ml of ethanol and stirred at 70° C. for 4 htogether with 500 mg of toluene-4-sulfonic acid. The mixture issubsequently evaporated in vacuo, taken up in 50 ml of ethyl acetate andwashed with 50 ml of water. The organic phase is dried over sodiumsulfate, filtered off and evaporated to dryness. Yield: 5.5 g (94%) ofethyl 2-(2,3-dioxoindolin-5-yl)pentanoate; LC-MS retention time: 2.08min.

Step 6:5-(1-Ethoxycarbonylbutyl)-1-tert-butoxycarbonyl-2,3-dioxoindoline

4.80 g of di-tert-butyl dicarbonate are added to 5.5 g of ethyl2-(2,3-dioxoindolin-5-yl)pentanoate and 50 mg of 4-dimethylaminopyridinein 100 ml of tetrahydrofuran, and the mixture is subsequently stirred at23° C. for 12 h. The mixture is evaporated at 23° C. in vacuo andprocessed further directly. Yield: 7.3 g (99%) of5-(1-ethoxycarbonylbutyl)-1-tert-butoxycarbonyl-2,3-dioxoindoline; LC-MSretention time: 2.42 min (“nonpolar” gradient).

Step 7: Ethyl2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]pentanoate

1.12 g of isoindoline are added to 3.5 g of5-(1-ethoxycarbonylbutyl)-1-tertbutoxycarbonyl-2,3-dioxoindoline in 50ml of tetrahydrofuran, and the mixture is subsequently stirred at 23° C.for 1 h. The mixture is evaporated to dryness in vacuo and purified bycolumn chromatography, giving 1.4 g (30%) of ethyl2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]-pentanoate;LC-MS retention time: 2.78 min (“nonpolar” gradient).

Step 8: Ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-pentanoate

1.4 g of ethyl2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]pentanoateare dissolved in 50 ml of acetonitrile under argon. 431 mg of caesiumfluoride and 769 μl of bis(trimethylsilyl)carbodiimide are added to thesolution. The mixture is stirred at room temperature for 15 min, and 6ml of hydrochloric acid (1N) are then added, and the mixture isneutralised using bicarbonate. The aqueous phase is washed three timeswith 100 ml of ethyl acetate each time. The combined organic phases aredried over sodium sulfate, filtered and evaporated to dryness in vacuo.Yield: 1.1 g (92%) of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]pentanoate (oil);LC-MS retention time: 1.84 min (“nonpolar” gradient).

Step 9: 2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]pentanoicacid

1.2 g of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]pentanoate aredissolved in 15 ml of tetrahydrofuran, and 10 ml of 2N sodium hydroxidesolution are added. The mixture is stirred at 50° C. for 4 h andsubsequently evaporated in vacuo. The mixture is then adjusted to pH2using 25% hydrochloric acid with ice-cooling, with yellow crystalsprecipitating. The precipitate obtained is filtered off and dried invacuo. Yield: 800 mg (72%) of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]pentanoic acid;LC-MS retention time: 1.40 min (“nonpolar” gradient).

EXAMPLE 12 Preparation of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]hexanoic acid(“A65”)

Step 1: Ethyl 2-(4-nitrophenyl)hexanoate

10.46 g of ethyl 4-nitrophenylacetate are dissolved in 30 ml of DMF,added dropwise to a suspension of 2.0 g of sodium hydride in 20 ml ofDMF with ice-cooling and stirred for 30 min. 5.394 ml of 1-bromobutanein 20 ml of DMF are subsequently added, and the mixture is stirred at23° C. for 12 h. The reaction mixture is subsequently stirred into 100ml of saturated ammonium chloride solution. The mixture is washed 4times with 100 ml of ethyl acetate each time, the combined organicphases with 100 ml of sodium chloride solution, dried over sodiumsulfate and, after filtration, evaporated to dryness in vacuo. Theresidue is purified by column chromatography (reversed phase). Yield: 11g (83%) of ethyl 2-(4-nitrophenyl)hexanoate; LC-MS retention time: 2.44min (“nonpolar” gradient).

Step 2: Ethyl 2-(4-aminophenyl)hexanoate

5.5 g of ethyl 2-(4-nitrophenyl)hexanoate are dissolved in 55 ml oftetrahydrofuran, 1 g of 5% Pd/C (52.3% of water) is added, and themixture is stirred at 23° C. under a hydrogen atmosphere for 1 h. Afteraeration, the solid material is filtered off, and the filtrate isevaporated to dryness in vacuo. Yield: 4.8 g (99%) of ethyl2-(4-aminophenyl)hexanoate (oil); LC-MS retention time: 1.73 min(“nonpolar” gradient).

Step 3: Ethyl 2-[4-[[(2Z/E)-2-hydroxyiminoacetyl]amino]phenyl]hexanoate

4.135 g of chloral hydrate are dissolved in 50 ml of water, 6.11 g ofNa₂SO₄ are added, and the mixture is stirred at 23° C. for 10 min. Asolution of 4.8 g of ethyl 2-(4-aminophenyl)hexanoate hydrochloride in50 ml of water is added to this solution. 5.11 g of hydroxylammoniumchloride in 20 ml of water are added to the resultant suspension, andthe mixture is stirred at 60° C. for 5 h. The mixture is subsequentlyallowed to cool, during which an orange oil deposits. This mixture iswashed three times with 50 ml of dichloromethane each time, the combinedorganic phases are dried over sodium sulfate, filtered off andevaporated to dryness in vacuo. The mixture obtained is employed in thefollowing reaction without further purification. Yield: 5.0 g (80%) ofethyl 2-[4-[[(2Z/E)-2-hydroxyiminoacetyl]amino]phenyl]hexanoate;

LC-MS retention time: 1.92 min (“nonpolar” gradient).

Step 4: Ethyl 2-(2,3-dioxoindolin-5-yl)hexanoate

30 ml of sulfuric acid (98%) are added in portions to 6.2 g of ethyl2-[4-[[(2Z/E)-2-hydroxyiminoacetyl]amino]phenyl]hexanoate, during whichthe temperature rises to 60° C. When the addition is complete, themixture is stirred at 50° C. for a further 120 min and subsequentlypoured into 400 ml of ice-water. The mixture is washed three times with200 ml of dichloromethane/ethanol (9:1) each time, the combined organicphases are dried over sodium sulfate, filtered off and evaporated todryness in vacuo. The crude product obtained is employed in the nextreaction without further purification. Yield: 5.6 g (mixture of ethyl2-(2,3-dioxoindolin-5-yl)hexanoate and 2-(2,3-dioxoindolin-5-yl)hexanoicacid in the ratio 1:3.5); LC-MS retention time: 1.89 min (ester) and1.35 min (acid) (“nonpolar” gradient).

Step 5: Ethyl 2-(2,3-dioxoindolin-5-yl)hexanoate

The resultant mixture of ethyl 2-(2,3-dioxoindolin-5-yl)hexanoate and2-(2,3-dioxoindolin-5-yl)pentanoic acid (5.6 g) from the precedingreaction is dissolved in 100 ml of ethanol and stirred at 70° C. for 4 htogether with 500 mg of toluene-4-sulfonic acid. The mixture issubsequently evaporated in vacuo, taken up in 50 ml of ethyl acetate andwashed with 50 ml of water. The organic phase is dried over sodiumsulfate, filtered off and evaporated to dryness.

Yield: 4.8 g (79%) of ethyl 2-(2,3-dioxoindolin-5-yl)hexanoate; LC-MSretention time: 1.89 min (“nonpolar” gradient).

Step 6:5-(1-Ethoxycarbonylpentyl)-1-tert-butoxycarbonyl-2,3-dioxoindoline

3.93 g of di-tert-butyl dicarbonate are added to 4.75 g of ethyl2-(2,3-dioxoindolin-5-yl)hexanoate and 50 mg of 4-dimethylaminopyridinein 100 ml of tetrahydrofuran, and the mixture is subsequently stirred at23° C. for 12 h. The mixture is evaporated at 23° C. in vacuo andprocessed further directly. Yield: 6.4 g (99%) of5-(1-ethoxycarbonylpentyl)-1-tert-butoxycarbonyl-2,3-dioxoindoline;LC-MS retention time: 2.55 min (“nonpolar” gradient).

Step 7: Ethyl2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]hexanoate

1.95 g of isoindoline are added to 6.4 g of5-(1-ethoxycarbonylpentyl)-1-tertbutoxycarbonyl-2,3-dioxoindoline in 100ml of tetrahydrofuran, and the mixture is subsequently stirred at 23° C.for 1 h. The mixture is evaporated to dryness in vacuo and purified bycolumn chromatography, giving 3.8 g (46%) of ethyl2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]hexanoate;LC-MS retention time: 2.89 min (“nonpolar” gradient).

Step 8: Ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]hexanoate

3.8 g of ethyl2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]hexanoateare dissolved in 100 ml of acetonitrile under argon. 1.12 g of caesiumfluoride and 2.01 ml of bis(trimethylsilyl)carbodiimide are added to thesolution. The mixture is stirred at room temperature for 15 min, and 6ml of hydrochloric acid (1N) are then added, and the mixture isneutralised using bicarbonate. The aqueous phase is washed three timeswith 100 ml of ethyl acetate each time. The combined organic phases aredried over sodium sulfate, filtered and evaporated to dryness in vacuo.Yield: 3.2 g (99%) of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]hexanoate (oil);

LC-MS retention time: 1.92 min (“nonpolar” gradient).

Step 9: 2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]hexanoicacid

1.0 g of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]hexanoate aredissolved in 15 ml of tetrahydrofuran, and 10 ml of 2N sodium hydroxidesolution are added. The mixture is stirred at 50° C. for 4 h andsubsequently evaporated in vacuo. The mixture is then adjusted to pH2using 25% hydrochloric acid with ice-cooling, with yellow crystalsprecipitating. The precipitate obtained is filtered off and dried invacuo. Yield: 550 mg (59%) of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]hexanoic acid;

LC-MS retention time: 1.52 min (“nonpolar” gradient).

EXAMPLE 13 Preparation of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-(3,3-difluoropropyl)-5,5-difluoropentanoicacid (“A66”)

Step 1: Ethyl 2-(4-aminophenyl)-5,5-difluoropent-4-enoate and ethyl4-aminophenyl)-2-(3,3-difluoroallyl)-5,5-difluoropent-4-enoate

7.113 g of ethyl 4-nitrophenylacetate are dissolved in 60 ml of DMF,added dropwise to a suspension of 3.4 g of sodium hydride in 40 ml ofDMF with ice-cooling and stirred for 30 min. 8.8 g of1,3-dibromo-1,1,-difluoropropane are subsequently added, and the mixtureis stirred at 23° C. for 12 h. The reaction mixture is subsequentlystirred into 100 ml of saturated ammonium chloride solution. The mixtureis washed four times with 100 ml of ethyl acetate each time, thecombined organic phases with 100 ml of sodium chloride solution, driedover sodium sulfate and, after filtration, evaporated to dryness invacuo. The residue is purified by column chromatography (reversedphase). Yield: 5.4 g (56%) of ethyl2-(4-aminophenyl)-5,5-difluoropent-4-enoate; LC-MS retention time: 2.21min (“nonpolar” gradient);

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 8.26-8.22 (m, 2H), 7.60-7.53(m, 2H), 4.18 (q, J=7.1, 2H), 2.82-2.68 (m, 3H), 1.99 (s, 1H), 1.17 (t,J=7.1, 3H)

and 2.4 g (25%) of ethyl4-aminophenyl)-2-(3,3-difluoroallyl)-5,5-difluoropent-4-enoate; LC-MSretention time: 2.49 min (“nonpolar” gradient);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 8.25-8.19 (m, 2H), 7.63-7.57 (m, 2H),4.04 (q, J=7.2, 2H), 2.74-2.64 (m, 1H), 2.51 (dt, J=3.7, 1.8, 2H),2.49-2.39 (m, 1H), 1.18 (t, J=7.2, 2H), 1.14 (t, J=7.1, 3H).

Step 2: Ethyl2-(4-aminophenyl)-2-(3,3-difluoropropyl)-5,5-difluoropentanoate

2.4 g of ethyl2-(4-aminophenyl)-2-(3,3-difluoroallyl)-5,5-difluoropent-4-enoate aredissolved in 30 ml of tetrahydrofuran, 1 g of 5% Pd/C (52.3% of water)is added, and the mixture is stirred at 23° C. under a hydrogenatmosphere for 1 h. After aeration, the solid material is filtered off,and the filtrate is evaporated to dryness in vacuo. Yield: 2.3 g (99%)of ethyl2-(4-aminophenyl)-2-(3,3-difluoropropyl)-5,5-difluoropentanoate; LC-MSretention time: 2.09 min.

Step 3: Ethyl2-(3,3-difluoropropyl)-5,5-difluoro-2-[4-[[(2E)-2-hydroxyiminoacetyl]amino]phenyl]pentanoate

1.241 g of chloral hydrate are dissolved in 15 ml of water, 1.99 g ofNa₂SO₄ are added, and the mixture is stirred at 23° C. for 10 min. Asolution of 7.55 g of ethyl 2-(4-aminophenyl)-2-methylpropanoatehydrochloride in 50 ml of water is added to this solution. 2.3 g ofhydroxylammonium chloride in 10 ml of water are added to the resultantsuspension, and the mixture is stirred at 60° C. for 5 h. The mixture issubsequently allowed to cool, during which an orange oil deposits. Thismixture is washed three times with 50 ml of dichloromethane each time,the combined organic phases are dried over sodium sulfate, filtered offand evaporated to dryness in vacuo. The mixture obtained is employed inthe following reaction without further purification.

Yield: 2.4 g (86%) of ethyl2-(3,3-difluoropropyl)-5,5-difluoro-2-[4-[[(2E)-2-hydroxyiminoacetyl]amino]phenyl]pentanoate;

LC-MS retention time: 1.86 min

Step 4: Ethyl2-(3,3-difluoropropyl)-2-(2,3-dioxoindolin-5-yl)-5,5-difluoropentanoate

3.0 g of ethyl2-(3,3-difluoropropyl)-5,5-difluoro-2-[4-[[(2E)-2-hydroxyiminoacetyl]amino]phenyl]pentanoateare added in portions to 20 ml of sulfuric acid (98%) at 50° C., duringwhich the temperature rises to 60° C. When the addition is complete, themixture is stirred at 50° C. for a further 120 min and subsequentlypoured into 400 ml of ice-water. The mixture is washed three times with200 ml of dichloromethane/ethanol (9:1) each time, the combined organicphases are dried over sodium sulfate, filtered off and evaporated todryness in vacuo. The crude product obtained is employed in the nextreaction without further purification. Yield: 1.9 g (66%) of ethyl2-(3,3-difluoropropyl)-2-(2,3-dioxoindolin-5-yl)-5,5-difluoropentanoateobtained; LC-MS retention time: 2.17 min.

Step 5:5-[1-(3,3-Difluoropropyl)-1-ethoxycarbonyl-4,4-difluorobutyl]-1-tertbutoxycarbonyl-2,3-dioxoindoline

1.419 g of di-tert-butyl dicarbonate are added to 1.9 g of ethyl2-(3,3-difluoropropyl)-2-(2,3-dioxoindolin-5-yl)-5,5-difluoropentanoateand 50 mg of 4-dimethylaminopyridine in 50 ml of tetrahydrofuran, andthe mixture is subsequently stirred at 23° C. for 12 h. The mixture isevaporated at 23° C. in vacuo and processed further directly. Yield: 2.4g (99%) of5-[1-(3,3-difluoropropyl)-1-ethoxycarbonyl-4,4-difluorobutyl]-1-tert-butoxycarbonyl-2,3-dioxoindoline;

LC-MS retention time: 2.38 min (“nonpolar” gradient).

Step 6: Ethyl2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]-2-(3,3-difluoropropyl)-5,5-difluoropentanoate

584 mg of isoindoline are added to 2.4 g of5-[1-(3,3-difluoropropyl)-1-ethoxycarbonyl-4,4-difluorobutyl]-1-tert-butoxycarbonyl-2,3-dioxoindolinein 30 ml of tetrahydrofuran, and the mixture is subsequently stirred at23° C. for 1 h. The mixture is evaporated to dryness in vacuo andpurified by column chromatography, giving 700 mg (24%) of ethyl2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]-2-(3,3-difluoropropyl)-5,5-difluoropentanoate;

LC-MS retention time: 2.72 min (“nonpolar” gradient).

Step 7: Ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-(3,3-difluoropropyl)-5,5-difluoropentanoate

700 mg of ethyl2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]-2-methylpropanoateare dissolved in 20 ml of acetonitrile under argon. 175 mg of caesiumfluoride and 317 μl of bis(trimethylsilyl)carbodiimide are added to thesolution. The mixture is stirred at room temperature for 15 min, and 3ml of hydrochloric acid (1N) are then added, and the mixture isneutralised using bicarbonate. The aqueous phase is washed three timeswith 100 ml of ethyl acetate each time. The combined organic phases aredried over sodium sulfate, filtered and evaporated to dryness in vacuo.Yield: 630 mg (100%) of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylpropanoate(oil); LC-MS retention time: 2.29 min (“nonpolar” gradient).

Step 8:2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-(3,3-difluoropropyl)-5,5-difluoropentanoicacid

500 mg of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-(3,3-difluoropropyl)-5,5-difluoropentanoateare dissolved in 7 ml of tetrahydrofuran, and 5 ml of 2N sodiumhydroxide solution are added. The mixture is stirred at 50° C. for 4 hand subsequently evaporated in vacuo. The mixture is then adjusted topH2 using 3 ml of 25% hydrochloric acid with ice-cooling, with yellowcrystals precipitating. The precipitate obtained is filtered off anddried in vacuo. Yield: 170 mg (36%) of2-[2-2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-(3,3-difluoropropyl)-5,5-difluoropentanoicacid;

LC-MS retention time: 1.58 min (“nonpolar” gradient).

EXAMPLE 14 Preparation of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl-2-methylpentanoicacid (“A67”)

Step 1: 2-Methyl-2-(4-nitrophenyl)pentanoic acid

10 g of ethyl 4-nitrophenylacetate are dissolved in 30 ml of DMF, addeddropwise to a suspension of 2.1 g of sodium hydride in 20 ml of DMF withice-cooling and stirred for 30 min. 3 ml of methyl iodide aresubsequently added, and the mixture is stirred at 23° C. for 12 h. Thereaction mixture is subsequently stirred into 100 ml of saturatedammonium chloride solution. The mixture is washed four times with 100 mlof ethyl acetate each time, the combined organic phases with 100 ml ofsodium chloride solution, dried over sodium sulfate and, afterfiltration, evaporated to dryness in vacuo. The residue is purified bycolumn chromatography (reversed phase). Yield: 6.7 g (33%) of2-methyl-2-(4-nitrophenylpentanoic acid; LC-MS retention time: 2.33 min.

Step 2: 2-Methyl-2-(4-nitrophenyl)pentanoic acid

3.35 g of 2-methyl-2-(4-nitrophenyl)pentanoic acid are dissolved in 20ml of DMF, added dropwise to a suspension of 720 mg of sodium hydride in10 ml of DMF with ice-cooling and stirred for 30 min. 1.55 ml of1-bromopropane are subsequently added, and the mixture is stirred at 23°C. for 12 h. The reaction mixture is subsequently stirred into 25 ml ofsaturated ammonium chloride solution. The mixture is washed four timeswith 25 ml of ethyl acetate each time, the combined organic phases with50 ml of sodium chloride solution, dried over sodium sulfate and, afterfiltration, evaporated to dryness in vacuo. The residue is purified bycolumn chromatography (reversed phase). Yield: 2.7 g (68%) of2-methyl-2-(4-nitrophenyl)pentanoic acid; LC-MS retention time: 2.50min;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 8.24-8.17 (m, 2H), 7.60-7.54 (m, 2H),4.12 (q, J=7.0, 2H), 2.00-1.87 (m, 2H), 1.53 (s, 3H), 1.19 (t, J=7.1,2H), 1.14 (t, J=7.1, 3H), 0.89 (t, J=7.3, 3H).

Step 3: Ethyl 2-(4-aminophenyl)-2-methylpentanoate

2.6 g of 2-methyl-2-(4-nitrophenyl)pentanoic acid are dissolved in 30 mlof tetrahydrofuran, 1 g of 5% Pd/C (52.3% of water) is added, and themixture is stirred at 23° C. under a hydrogen atmosphere for 1 h. Afteraeration, the solid material is filtered off, and the filtrate isevaporated to dryness in vacuo. Yield: 2.2 g (95%) of ethyl2-(4-aminophenyl)-2-methylpropanoate; LC-MS retention time: 1.99 min.

Step 4: Ethyl2-[4-[[(2E)-2-hydroxyiminoacetyl]amino]phenyl]-2-methylpentanoate

1.819 g of chloral hydrate are dissolved in 20 ml of water, 2.841 g ofNa₂SO₄ are added, and the mixture is stirred at 23° C. for 10 min. Asolution of 2.3 g of ethyl 2-(4-aminophenyl)-2-methylpentanoatehydrochloride in 20 ml of water is added to this solution. 2.1 g ofhydroxylammonium chloride in 10 ml of water are added to the resultantsuspension, and the mixture is stirred at 60° C. for 4 h. The mixture issubsequently allowed to cool, during which an orange oil deposits. Thismixture is washed three times with 50 ml of dichloromethane each time,the combined organic phases are dried over sodium sulfate, filtered offand evaporated to dryness in vacuo. The mixture obtained is employed inthe following reaction without further purification.

Yield: 2.8 g (94%) of ethyl2-[4-[[(2E)-2-hydroxyiminoacetyl]amino]phenyl]-2-methylpentanoate; LC-MSretention time: 2.23 min.

Step 5: Ethyl 2-(2,3-dioxoindolin-5-yl)-2-methylpentanoate

2.8 g of ethyl2-[4-[[(2E)-2-hydroxyiminoacetyl]amino]phenyl]-2-methylpropanoate areadded in portions to 15 ml of sulfuric acid (98%) at 50° C., duringwhich the temperature rises to 60° C. When the addition is complete, themixture is stirred at 50° C. for a further 120 min and subsequentlypoured into 100 ml of ice-water. The mixture is washed 3 times with 50ml of dichloromethane/ethanol (9:1) each time, the combined organicphases are dried over sodium sulfate, filtered off and evaporated todryness in vacuo. The crude product obtained is employed in the nextreaction without further purification. Yield: 1.2 g (35%) of ethyl2-(2,3-dioxoindolin-5-yl)-2-methylpentanoate; LC-MS retention time: 2.23min.

Step 6:5-(2-Ethoxy-1-methylbutyl-2-oxoethyl))-1-tert-butoxycarbonyl-2,3-dioxoindoline

1.0 g of di-tert-butyl dicarbonate are added to 1.2 g of ethyl2-(2,3-dioxoindolin-5-yl)-2-methylpentanoate and 50 mg of4-dimethylaminopyridine in 30 ml of tetrahydrofuran, and the mixture issubsequently stirred at 23° C. for 12 h. The mixture is evaporated at23° C. in vacuo and processed further directly. Yield: 1.6 g (99%) of5-(2-ethoxy-1-methylbutyl-2-oxoethyl))-1-tertbutoxycarbonyl-2,3-dioxoindoline;LC-MS retention time: 2.82 min.

Step 7: Ethyl2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]-2-methylpentanoate

0.489 g of isoindoline are added to 1.6 g of5-(2-ethoxy-1-methylbutyl-2-oxoethyl))-1-tert-butoxycarbonyl-2,3-dioxoindolinein 20 ml of tetrahydrofuran, and the mixture is subsequently stirred at23° C. for 1 h. The mixture is evaporated to dryness in vacuo andpurified by column chromatography, giving 200 mg (10%) of ethyl2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]-2-methylpentanoate;

LC-MS retention time: 2.98 min (“nonpolar” gradient).

Step 8: Ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl-2-methylpentanoate

200 mg of ethyl2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]-2-methylpentanoateare dissolved in 10 ml of acetonitrile under argon. 61 mg of caesiumfluoride and 106 μl of bis(trimethylsilyl)carbodiimide are added to thesolution. The mixture is stirred at room temperature for 15 min, and 6ml of hydrochloric acid (1N) are then added, and the mixture isneutralised using bicarbonate. The aqueous phase is washed three timeswith 20 ml of ethyl acetate each time. The combined organic phases aredried over sodium sulfate, filtered and evaporated to dryness in vacuo.Yield: 150 mg (88%) of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylpentanoate(oil); LC-MS retention time: 1.97 min (“nonpolar” gradient).

Step 9:2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl-2-methylpentanoicacid

150 mg of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl-2-methylpentanoateare dissolved in 2 ml of tetrahydrofuran, and 2 ml of 2N sodiumhydroxide solution are added. The mixture is stirred at 50° C. for 12 h,and tetrahydrofuran is subsequently stripped off in vacuo. The mixtureis diluted with 4 ml of water and then adjusted dropwise to pH2 using25% hydrochloric acid with ice-cooling, with yellow crystalsprecipitating. The precipitate obtained is filtered off and dried invacuo. Yield: 80 mg (57%) of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl-2-methylpentanoicacid;

LC-MS retention time: 1.51 min.

EXAMPLE 15 Preparation of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclopentanecarboxylicacid (“A68”)

188 mg of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetate aresuspended in 1 ml of DMF, and 60 μl of 1,4-dibromobutane are added. 80mg of sodium hydride are subsequently added with ice-cooling, and themixture is stirred with cooling for a further 30 min. After 1 h at 23°C., the mixture is re-cooled, and a further 10 mg of sodium hydride areadded to the mixture. The mixture is stirred at 23° C. for a further 30min, 1 ml of 2N sodium hydroxide solution is added, and the mixture isstirred at 70° C. for 12 h. After cooling to 23° C., the mixture isacidified by dropwise addition of 1N hydrochloric acid, with a yellowprecipitate forming. This is filtered off, washed with water and driedat 50° C. for 12 h.

Yield: 83 mg (41%) of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-cyclopentanecarboxylicacid; LC-MS retention time: 2.13 min.

EXAMPLE 16 Preparation of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]tetrahydropyran-4-carboxylic acid (“A69”)

188 mg of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetate aresuspended in 1 ml of DMF, and 1 ml of bis(2-bromoethyl)ether is added.80 mg of sodium hydride are subsequently added with ice-cooling, and themixture is stirred with cooling for a further 30 min. After 1 h at 23°C., the mixture is re-cooled, and a further 10 mg of sodium hydride areadded to the mixture. The mixture is stirred at 23° C. for a further 30min, 1 ml of 2N sodium hydroxide solution is added, and the mixture isstirred at 70° C. for 12 h. After cooling to 23° C., the mixture isacidified by dropwise addition of 1N hydrochloric acid, with a yellowprecipitate forming. This is filtered off, washed with water and driedat 50° C. for 12 h.

Yield: 50 mg (24%) of2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-tetrahydropyran-4-carboxylicacid; LC-MS retention time: 2.01 min.

EXAMPLE 17 Preparation of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-5-methylhexanoicacid (“A70”)

94 mg of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetate aresuspended in 1 ml of DMF, and 31 μl of 1-bromo-3-methylbutane are added.10 mg of sodium hydride are subsequently added with ice-cooling, and themixture is stirred with cooling for a further 30 min. After 1 h at 23°C., the mixture is re-cooled, and a further 10 mg of sodium hydride areadded to the mixture. The mixture is stirred at 23° C. for a further 30min, 1 ml of 2N sodium hydroxide solution is added, and the mixture isstirred at 60° C. for 12 h. After cooling to 23° C., the mixture isacidified by dropwise addition of 1N hydrochloric acid, with a yellowprecipitate forming. This is filtered off, washed with water and driedat 50° C. for 12 h.

Yield: 48 mg (46%) of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-5-methylhexanoicacid; LC-MS retention time: 2.05 min.

EXAMPLE 18 Preparation of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-4-methylpentanoicacid (“A71”)

188 mg of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetate aresuspended in 1 ml of DMF, and 54 μl of 1-bromo-2-methylpropane areadded. 20 mg of sodium hydride are subsequently added with ice-cooling,and the mixture is stirred with cooling for a further 30 min. After 1 hat 23° C., the mixture is re-cooled, and a further 20 mg of sodiumhydride are added to the mixture. The mixture is stirred at 23° C. for afurther 30 min, 1 ml of 2N sodium hydroxide solution is added, and themixture is stirred at 60° C. for 12 h. After cooling to 23° C., themixture is acidified by dropwise addition of 1N hydrochloric acid, witha yellow precipitate forming. This is filtered off, washed with waterand dried at 50° C. for 12 h.

Yield: 139 mg (69%) of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]4-methylpentanoicacid; LC-MS retention time: 1.93 min.

EXAMPLE 19 Preparation of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-3-methylpentanoicacid (“A72”)

188 mg of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetate aresuspended in 1 ml of DMF, and 54 μl of 1-bromobutane are added. 20 mg ofsodium hydride are subsequently added with ice-cooling, and the mixtureis stirred with cooling for a further 30 min. After 1 h at 23° C., themixture is recooled, and a further 20 mg of sodium hydride are added tothe mixture. The mixture is stirred at 23° C. for a further 30 min, 1 mlof 2N sodium hydroxide solution is added, and the mixture is stirred at60° C. for 12 h. After cooling to 23° C., the mixture is acidified bydropwise addition of 1N hydrochloric acid, with a yellow precipitateforming. This is filtered off, washed with water and dried at 50° C. for12 h.

Yield: 81 mg (40%) of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-3-methylpentanoicacid; LC-MS retention time: 1.91 min.

EXAMPLE 20 Preparation of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-3-methylbutanoicacid (“A73”)

188 mg of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetate aresuspended in 1 ml of DMF, and 54 μl of 2-bromopropane are added. 20 mgof sodium hydride are subsequently added with ice-cooling, and themixture is stirred with cooling for a further 30 min. After 1 h at 23°C., the mixture is re-cooled, and a further 20 mg of sodium hydride areadded to the mixture. The mixture is stirred at 23° C. for a further 30min, 1 ml of 2N sodium hydroxide solution is added, and the mixture isstirred at 60° C. for 12 h. After cooling to 23° C., the mixture isacidified by dropwise addition of 1N hydrochloric acid, with a yellowprecipitate forming. This is filtered off, washed with water and driedat 50° C. for 12 h.

Yield: 78 mg (40%) of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-3-methylbutanoicacid; LC-MS retention time: 1.81 min.

EXAMPLE 21 Preparation of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-4-carbamoylpent-4-enoicacid (“A74”)

“A74” is obtained in accordance with the following scheme:

Step 1: O1-tert-Butyl O5-ethyl4-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylenepentanedioate

1 g of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetate aresuspended in 10 ml of DMF, and 1 g of tert-butyl3-bromo-2-(bromomethyl)propanoate is added. 324 mg of sodium hydride aresubsequently added with ice-cooling, and the mixture is stirred withcooling for a further 30 min. After 1 h at 23° C., the mixture is pouredinto 50 ml of saturated ammonium chloride solution, with a precipitateforming. This is filtered off, washed with water and dried at 50° C. for12 h. Yield: 900 mg (66%) of O1-tert-butyl O5-ethyl4-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylenepentanedioate;

LC-MS retention time: 2.40 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 7.97 (dd, J=8.8, 1.8, 1H), 7.89(d, J=1.7, 1H), 7.72 (d, J=8.8, 1H), 7.39 (d, J=7.5, 1H), 7.26 (dt,J=23.3, 7.1, 2H), 7.16 (d, J=7.5, 1H), 5.87 (s, 1H), 5.40 (s, 1H), 5.00(s, 2H), 4.75 (s, 2H), 3.98 (q, J=7.2, 2H), 1.90 (s, 9H), 1.32 (s, 1H),1.12 (t, J=7.2, 3H).

Step 2:4-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylenepentanedioicacid O5-ethyl ester

200 μl of trifluoroacetic acid are added to 100 mg of O1-tert-butylO5-ethyl4-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylenepentanedioatein 1 ml of dichloromethane, and the mixture is stirred at 23° C. for 3h. The mixture is subsequently evaporated to dryness in vacuo andreacted further directly.

Yield: 70 mg (76%) of4-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylenepentanedioicacid O5-ethyl ester; LC-MS retention time: 1.80 min.

Step 3: Ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-4-carbamoylpent-4-enoate

1 ml of thionyl chloride is added at 23° C. to 90 mg of4-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylenepentanedioicacid O5-ethyl ester, and the mixture is stirred for 1 h. The mixture issubsequently evaporated at 40° C. in vacuo, taken up in 1 ml oftetrahydrofuran, and 1 ml of a 0.5 M ammonia solution in dioxane isadded. After 30 min, the mixture is evaporated in vacuo and employeddirectly in the next reaction. Yield: 89 mg (99%) of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-4-carbamoylpent-4-enoate;

LC-MS retention time: 1.66 min.

Step 4:1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-4-carbamoylpent-4-enoicacid (“A74”)

89 mg of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-4-carbamoylpent-4-enoicacid are dissolved 0.5 ml of tetrahydrofuran and 0.5 ml of methanol. 1ml of 2N sodium hydroxide solution is added to this solution, and themixture is stirred at 23° C. for 2 h. The mixture is then acidified bydropwise addition of 1N hydrochloric acid, with a yellow precipitateforming. This is filtered off, washed with water and dried at 50° C. for12 h. Yield: 69 mg (83%) of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-4-carbamoylpent-4-enoicacid; LC-MS retention time: 1.39 min.

EXAMPLE 22 Preparation of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-4-(4-methylpiperazin-1-yl)-4-oxobutanoicacid (“A75”)

188 mg of ethyl2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetate aresuspended in 1 ml of DMF, and 109 mg of2-chloro-1-(4-methylpiperazin-1-yl)ethanone are added. 30 mg of sodiumhydride are subsequently added with ice-cooling, and the mixture isstirred with cooling for a further 30 min. After 1 h at 23° C., themixture is re-cooled, and a further 30 mg of sodium hydride are added tothe mixture. The mixture is stirred at 23° C. for a further 30 min, 1 mlof 2N sodium hydroxide solution is added, and the mixture is stirred at60° C. for 12 h. After cooling to 23° C., the mixture is acidified bydropwise addition of 1N hydrochloric acid, with a yellow precipitateforming. This is filtered off, washed with water and dried at 50° C. for12 h.

Yield: 210 mg (86%) of1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-4-(4-methylpiperazin-1-yl)-4-oxobutanoicacid; LC-MS retention time: 1.05 min.

EXAMPLE 23 Preparation of[2-amino-6-[(4-methylpiperazin-1-yl)methyl]quinazolin-4-yl]-isoindolin-2-ylmethanone(“A76”)

75 mg of (2-amino-6-iodoquinazolin-4-yl)isoindolin-2-ylmethanone aresuspended in 2 ml of tetrahydrofuran and 7 μl of water together with 40mg of potassium 1-methyl-4-trifluoroboratomethylpiperazine, 1 mg ofpalladium diacetate, 4 mg of ((2,4,6triisopropyl)phenyl)dicyclohexylphosphine and 176 mg of caesiumcarbonate, and the mixture is stirred at 80° C. for 48 h. After cooling,the mixture is filtered through kieselguhr, rinsed three times with 5 mlof tetrahydrofuran each time, and the filtrate is evaporated to dry nessin vacuo. The residue is purified by means of preparative HPLC, and thetitle compound is isolated.

Yield: 42 mg (53%) of[2-amino-6-[(4-methylpiperazin-1-yl)methyl]quinazolin-4-yl]isoindolin-2-ylmethanone;LC-MS retention time: 1.14 min;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 8.33 (d, J=1.7, 1H), 8.23 (dd,J=8.7, 1.7, 1H), 7.83 (d, J=8.6, 1H), 7.45 (d, J=7.5, 1H), 7.31 (dt,J=21.5, 7.2, 2H), 7.22 (d, J=7.5, 1H), 5.03 (s, 2H), 4.81 (s, 2H), 4.59(s, 2H), 3.75-3.26 (m, 8H), 2.84 (s, 3H).

The following compounds are obtained analogously to the preparation ofthe above-mentioned examples:

N-dimethyl-2-amino-6-(1-ethylcarbamoylcyclobutyl)quinazoline-4-carboxamide(“A77”)

Yield: 20 mg (15%) LC-MS retention time: 1.24 min;

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 8.05 (dd, J=8.8, 1.9, 1H), 7.75(d, J=8.7, 1H), 7.69 (d, J=1.8, 1H), 3.19 (s, 3H), 3.08 (q, J=7.2, 2H),2.96 (s, 3H), 2.85-2.77 (m, 2H), 2.41 (dt, J=11.9, 8.8, 2H), 1.96-1.74(m, 2H), 0.98 (t, J=7.2, 3H).

N-Methylpropyl-2-amino-6-(1-ethylcarbamoylcyclobutyl)quinazoline-4-carboxamide(“A78”)

Yield: 135 mg (43%) LC-MS retention time: 1.48 min;

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 8.06 (dd, J=8.7, 2.0, 1H), 7.75(dd, J=8.7, 2.7, 1H), 7.68 (dd, J=8.4, 1.9, 1H), 3.64-3.18 (m, 2H), 3.16(s, 2H), 3.09 (qd, J=7.2, 4.7, 2H), 2.93 (s, 2H), 2.80 (ddd, J=11.6,8.8, 4.3, 2H), 2.39 (ddd, J=11.9, 9.2, 4.6, 2H), 1.84-1.70 (m, 2H),1.98-1.50 (m, 2H), 0.98 (t, J=7.2, 3H), 1.07-0.69 (m, 2H).

N-Diethyl-2-amino-6-(1-ethylcarbamoylcyclobutyl)quinazoline-4-carboxamide(“A79”)

Yield: 51 mg (30%) LC-MS retention time: 1.48 min;

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 8.07 (dd, J=8.7, 2.0, 1H), 7.75(d, J=8.8, 1H), 7.65 (d, J=1.9, 1H), 3.64 (q, J=7.0, 2H), 3.28 (q,J=7.0, 2H), 3.08 (q, J=7.2, 2H), 2.80 (ddd, J=12.0, 8.8, 6.2, 2H), 2.37(dt, J=12.0, 8.9, 2H), 1.96-1.73 (m, 2H), 1.30 (t, J=7.1, 3H), 1.08 (t,J=7.0, 3H), 0.98 (t, J=7.2, 3H).

N-Benzylmethyl-2-amino-6-(1-ethylcarbamoylcyclobutyl)quinazoline-4-carboxamide(“A80”)

Yield: 48 mg (23%) LC-MS retention time: 1.72 min;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]-7.20 (m, 8H), 6.96 (s, 2H), 4.86-4.29(m, 2H), 3.28 (s, 3H), 3.08-2.99 (m, 2H), 2.72-2.63 (m, 2H), 2.38-2.19(m, 2H), 1.92-1.64 (m, 2H), 1.00-0.84 (m, 3H).

Ethyl1-[4-(tert-butoxycarbonylamino)-3-(dimethylaminooxalyl)phenyl]cyclobutanecarboxylate(“A81”)

Yield: 306 mg (49%)

LC-MS retention time: 2.46 min (“nonpolar” gradient);

¹H-NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] d, J=8.8, 1H), 7.67 (dd,J=8.8, 2.2, 1H), 7.43 (d, J=2.4, 1H), 4.08 (q, J=7.1, 2H), 3.05 (s, 3H),2.93 (s, 3H), 2.76 (ddd, J=12.1, 9.1, 5.7, 2H), 2.45-2.36 (m, 2H),2.06-1.79 (m, 3H), 1.52 (s, 9H), 1.14 (t, J=7.2, 3H).

Ethyl1-[4-(tert-butoxycarbonylamino)-3-(methylpropylaminooxalyl)phenyl]-cyclobutanecarboxylate(“A82”)

Yield: 260 mg (39%)

LC-MS retention time: 2.69 min (“nonpolar” gradient);

¹H-NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.42 (dd, J=8.9, 1.7, 1H),7.65 (td, J=9.0, 2.2, 1H), 7.47 (dd, J=18.8, 2.3, 1H), 4.07 (q, J=7.2,2H), 3.49-3.14 (m, 2H), 3.02-2.89 (m, 3H), 2.79-2.70 (m, 2H), 2.46-2.34(m, 2H), 2.05-1.74 (m, 2H), 1.72-1.53 (m, 2H), 1.52 (s, 9H), 1.13 (td,J=7.1, 2.8, 3H), 0.99-0.74 (m, 3H).

Ethyl1-[4-(tert-butoxycarbonylamino)-3-(diethylaminooxalyl)phenyl]-cyclobutanecarboxylate(“A83”)

Yield: 255 mg (45%)

LC-MS retention time: 2.68 min (“nonpolar” gradient);

¹H-NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.43 (d, J=9.0, 1H), 7.65 (dd,J=8.9, 2.3, 1H), 7.47 (d, J=2.2, 1H), 4.09-4.04 (m, 2H), 3.50 (q, J=7.1,2H), 3.24 (q, J=7.1, 2H), 2.75 (ddd, J=12.1, 8.9, 5.3, 2H), 2.39 (dt,J=12.1, 9.1, 2H), 2.04-1.80 (m, 2H), 1.52 (s, 9H), 1.23 (t, J=7.1, 3H),1.13 (t, J=7.1, 3H), 1.09 (t, J=7.0, 3H).

Ethyl1-[4-(tert-butoxycarbonylamino)-3-(benzylmethylaminooxalyl)phenyl]-cyclobutanecarboxylate(“A84”)

Yield: 322 mg (43%)

LC-MS retention time: 2.84 min (“nonpolar” gradient);

¹H-NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.40 (d, J=8.8, 1H), 7.65(ddd, J=15.8, 8.8, 2.3, 1H), 7.50 (dd, J=24.4, 2.2, 1H), 7.45-7.22 (m,5H), 4.73-4.49 (m, 2H), 4.12-3.99 (m, 2H), 2.95-2.87 (m, 3H), 2.74(dddd, J=24.4, 11.9, 8.8, 5.3, 2H), 2.43-2.27 (m, 2H), 2.04-1.74 (m,2H), 1.52-1.49 (m, 9H), 1.17-1.05 (m, 3H).

Ethyl1-[4-(tert-butoxycarbonylamino)-3-(methylphenylaminooxalyl)phenyl]-cyclobutanecarboxylate(“A85”)

Yield: 311 mg (43%)

LC-MS retention time: 2.74 min (“nonpolar” gradient);

¹H-NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.24 (d, J=8.8, 1H), 7.66-7.51(m, 2H), 7.34-7.24 (m, 3H), 7.22-7.17 (m, 2H), 4.11 (q, J=7.2, 2H), 3.43(s, 3H), 2.79 (ddd, J=12.1, 8.9, 5.6, 2H), 2.43 (dt, J=12.1, 9.1, 2H),2.06-1.81 (m, 2H), 1.46 (s, 9H), 1.16 (t, J=7.2, 3H).

Ethyl1-[4-(tert-butoxycarbonylamino)-3-(4-methylpiperazin-1-yl)-2-oxo-acetyl]phenyl]cyclobutanecarboxylate(“A86”)

Yield: 296 mg (42%)

LC-MS retention time: 1.42 min (“nonpolar” gradient);

¹H-NMR (500 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 8.35 (d, J=8.8, 1H), 7.70 (dd,J=8.8, 2.2, 1H), 7.49 (d, J=2.4, 1H), 4.59 (d, J=13.6, 1H), 4.13-4.06(m, 2H), 3.92 (d, J=13.6, 1H), 3.70-3.58 (m, 2H), 3.47 (t, J=13.2, 1H),3.27 (d, J=12.3, 1H), 3.15 (d, J=11.4, 1H), 3.00 (s, 1H), 2.92 (s, 3H),2.82-2.72 (m, 2H), 2.44 (d, J=8.6, 2H), 2.08-1.74 (m, 2H), 1.52 (s, 9H),1.16 (t, J=7.1, 3H).

Ethyl1-(2-amino-4-dimethylcarbamoylquinazolin-6-yl)cyclobutanecarboxylate(“A87”)

Yield: 280 mg (100%)

LC-MS retention time: 1.67 min;

Ethyl1-(2-amino-4-(-methylpropylcarbamoyl)quinazolin-6-yl)cyclobutanecarboxylate(“A88”)

Yield: 240 mg (100%)

LC-MS retention time: 1.88 min;

Ethyl1-(2-amino-4-diethylcarbamoylquinazolin-6-yl)cyclobutanecarboxylate(“A89”)

Yield: 280 mg (100%)

LC-MS retention time: 1.89 min;

Ethyl1-(2-amino-4-(benzylmethylcarbamoyl)quinazolin-6-yl)cyclobutanecarboxylate(“A90”)

Yield: 305 mg (100%)

LC-MS retention time: 2.09 min;

¹H-NMR (400 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.97 (dt, J=8.9, 2.2, 1H),7.77 (dd, J=8.7, 5.6, 1H), 7.63 (dd, J=25.6, 1.8, 1H), 7.51-7.24 (m,5H), 4.12-3.99 (m, 2H), 3.63-3.20 (m, 2H), 3.16-2.92 (m, 4H), 2.88-2.72(m, 2H), 2.49-2.39 (m, 2H), 2.14-1.79 (m, 3H), 1.76-1.55 (m, 2H),1.17-1.05 (m, 3H).

Ethyl1-(2-amino-4-(4-methylpiperazine-1-carbonyl)quinazolin-6-yl)cyclobutanecarboxylate(“A91”)

Yield: 250 mg (100%)

LC-MS retention time: 1.33 min.

1-(2-Amino-4-dimethylcarbamoylquinazolin-6-yl)cyclobutanecarboxylic acid(“A92”)

Yield: 120 mg (26%)

LC-MS retention time: 1.32 min;

¹H-NMR (400 MHz, DMSO-d₆/TFA-d₁): δ [ppm]8.00-7.96 (m, 1H), 7.79-7.76(m, 1H), 7.62-7.58 (m, 1H), 3.19-2.96 (m, 6H), 2.88-2.71 (m, 2H),2.52-2.37 (m, 2H), 2.13-1.77 (m, 2H).

1-(2-Amino-4-(-methylpropylcarbamoyl)quinazolin-6-yl)cyclobutanecarboxylicacid (“A93”)

Yield: 125 mg (56%).

LC-MS retention time: 1.52 min;

¹H-NMR (400 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.99-7.95 (m, 1H), 7.79-7.74(m, 1H), 7.60-7.57 (m, 1H), 3.63-3.20 (m, 2H), 3.16-2.92 (m, 4H),2.88-2.72 (m, 2H), 2.49-2.39 (m, 2H), 2.14-1.79 (m, 3H), 1.76-1.55 (m,2H), 1.06-0.71 (m, 3H).

1-(2-Amino-4-diethylcarbamoylquinazolin-6-yl)cyclobutanecarboxylic acid(“A94”)

Yield: 157 mg (61%)

LC-MS retention time: 1.49 min;

¹H-NMR (400 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.97 (dd, J=8.8, 1.9, 1H),7.76 (d, J=8.8, 1H), 7.62 (d, J=1.9, 1H), 3.64 (q, J=7.0, 2H), 3.29 (q,J=6.8, 2H), 2.91-2.73 (m, 2H), 2.46 (dd, J=20.0, 8.9, 2H), 2.17-1.79 (m,2H), 1.31 (t, J=7.0, 3H), 1.11 (t, J=7.0, 3H).

1-(2-Amino-4-(benzylmethylcarbamoyl)quinazolin-6-yl)cyclobutanecarboxylicacid (“A95”)

Yield: 194 mg (68%)

LC-MS retention time: 1.71 min;

¹H-NMR (400 MHz, DMSO-d₆/TFA-d₁): δ [ppm] 7.99-7.94 (m, 1H), 7.80-7.74(m, 1H), 7.68-7.57 (m, 1H), 7.53-7.24 (m, 5H), 4.86-4.56 (m, 2H),3.09-2.92 (m, 3H), 2.91-2.76 (m, 2H), 2.52-2.34 (m, 2H), 2.16-1.76 (m,2H).

The following examples relate to pharmaceutical compositions:

EXAMPLE A Injection Vials

A solution of 100 g of an active ingredient according to the inventionand 5 g of disodium hydrogenphosphate in 3 l of bidistilled water isadjusted to pH 6.5 using 2 N hydrochloric acid, sterile filtered,transferred into injection vials, lyophilised under sterile conditionsand sealed under sterile conditions. Each injection vial contains 5 mgof active ingredient.

EXAMPLE B Suppositories

A mixture of 20 g of an active ingredient according to the inventionwith 100 g of soya lecithin and 1400 g of cocoa butter is melted, pouredinto moulds and allowed to cool. Each suppository contains 20 mg ofactive ingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of an active ingredient according to theinvention, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12; H₂O and 0.1 gof benzalkonium chloride in 940 ml of bidistilled water. The pH isadjusted to 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active ingredient according to the invention are mixed with99.5 g of Vaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient, 4 kg of lactose, 1.2 kg ofpotato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate ispressed in a conventional manner to give tablets in such a way that eachtablet contains 10 mg of active ingredient.

EXAMPLE F Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient are introduced into hard gelatine capsules ina conventional manner in such a way that each capsule contains 20 mg ofthe active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of an active ingredient according to the invention in60 l of bidistilled water is sterile filtered, transferred intoampoules, lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

The invention claimed is:
 1. A compound of formula I

in which R¹, R² each, independently of one another, denote H, A,(CH₂)_(n)Het or (CH₂)_(n)Ar, R¹ and R², together with the N atom towhich they are bonded, also denote a saturated, unsaturated or aromaticmono- or bicyclic heterocycle, which may contain a further 1 to 3 N, Oand/or S atoms and which is unsubstituted or mono-, di- ortrisubstituted by Hal, A, (CH₂)_(n)Het, (CH₂)_(n)Ar, (CH₂)_(n)OH,(CH₂)_(n)OA, (CH₂)_(n)NH₂, (CH₂)_(n)COOH, (CH₂)_(n)COOA, NHCOA, NA′COA,CONH₂, CONHA, CONAA′, OC(═O)(CH₂)_(p)NH₂ and/or ═O (carbonyl oxygen), R³and R⁴, together with the C atom to which they are bonded, denote asaturated or unsaturated monocyclic C3-C10-carbocycle, which may containa further 1 to 3 N, O and/or S atoms and which is unsubstituted ormono-, di- or trisubstituted by Hal, A, (CH₂)_(n)OH, (CH₂)_(n)OA,(CH₂)_(n)NH₂, (CH₂)_(n)COOH, (CH₂)_(n)COOA, NHCOA, NA′COA, CONH₂, CONHA,CONAA′, OC(═O)(CH₂)_(p)NH₂ and/or ═O (carbonyl oxygen), X denotes NR⁵R⁶,CONR⁵R⁶, CH₂NR⁵R⁶, COOR⁵, —OR⁵, CH₂OR⁵, COHet, Het, CONH(CH₂)_(p)CN orCONH(CH₂)_(p)NR⁵R⁶, R⁵, R⁶ each, independently of one another, denote H,A, (CH₂)_(n)Het or (CH₂)_(n)Ar, Ar denotes phenyl, naphthyl,tetrahydronaphthyl or biphenyl, each of which is unsubstituted or mono-,di-, tri-, tetra- or pentasubstituted by A, Hal, (CH₂)_(n)OA,(CH₂)_(n)OH, (CH₂)_(n)CN, SA, SOA, SO₂A, NO₂, C≡CH, (CH₂)_(n)COOH, CHO,(CH₂)_(n)COOA, CONH₂, CONHA, CONAA′, NHCOA, CH(OH)A, (CH₂)_(n)NH₂,(CH₂)_(n)NHA, (CH₂)_(n)NAA′, (CH₂)_(n)NHSO₂A, SO₂NH(CH₂)_(n)NH₂, SO₂NH₂,SO₂NHA, SO₂NAA′, CONH(CH₂)_(n)COOA, CONH(CH₂)_(n)COOH,NHCO(CH₂)_(n)COOA, NHCO(CH₂)_(n)COOH, CONH(CH₂)_(n)NH₂,CONH(CH₂)_(n)NHA, CONH(CH₂)_(n)NAA′, CONH(CH₂)_(n)CN and/or(CH₂)_(n)CH(NH₂)COOH, Het denotes a mono- or bicyclic saturated,unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms,which may be unsubstituted or mono-, di- or trisubstituted by A, OA, OH,phenyl, SH, S(O)_(m)A, Hal, NO₂, CN, COA, COOA, COObenzyl, CONH₂, CONHA,CONAA′, SO₂NH₂, NH₂, NHA, NAA′, NHCOA, NHSO₂A and/or ═O (carbonyloxygen), A, A′ each, independently of one another, denote unbranched orbranched alkyl having 1-10 C atoms, in which 1-3 non-adjacent CH₂ groupsmay be replaced by O, S, SO, SO₂, NH, NMe or Net, and/or, in addition,1-5 H atoms may be replaced by F and/or Cl, or cyclic alkyl having 3-8 Catoms, Hal denotes F, Cl, Br or I, n denotes 0, 1, 2, 3 or 4, p denotes1, 2, 3 or 4, or pharmaceutically usable salts, tautomers orstereoisomers thereof, including mixtures thereof in all ratios.
 2. Thecompound according to claim 1 in which R¹ and R², together with the Natom to which they are bonded, denotes an unsubstituted saturated,unsaturated or aromatic mono- or bicyclic heterocycle, which may containa further 1 to 2 N, O and/or S atoms, or pharmaceutically usable salts,tautomers or stereoisomers thereof, including mixtures thereof in allratios.
 3. The compound according to claim 1 in which R³ and R⁴,together with the C atom to which they are bonded, also denote anunsubstituted saturated monocyclic C3-C6-carbocycle, which may contain afurther 1 to 3 N, O and/or S atoms, or pharmaceutically usable salts,tautomers or stereoisomers thereof, including mixtures thereof in allratios.
 4. The compound according to claim 1 in which X denotes CONR⁵R⁶,COOR⁵, COHet, Het, CONH(CH₂)_(p)CN or CONH(CH₂)_(p)NR⁵R⁶, orpharmaceutically usable salts, tautomers or stereoisomers thereof,including mixtures thereof in all ratios.
 5. The compound according toclaim 1 in which R⁵, R⁶ each, independently of one another, denote H, Aor (CH₂)_(n)Het, or pharmaceutically usable salts, tautomers orstereoisomers thereof, including mixtures thereof in all ratios.
 6. Thecompound according to claim 1 in which Het denote pyridyl, pyrimidinyl,furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl,isoxazolyl, thiazolyl, piperazinyl, pyrazinyl, pyridazinyl, morpholinyl,azepanyl, azetidinyl, pyrrolidinyl or piperidinyl, each of which isunsubstituted or mono-, di- or trisubstituted by A, OA, OH, Hal, CNand/or ═O (carbonyl oxygen), or pharmaceutically usable salts, tautomersor stereoisomers thereof, including mixtures thereof in all ratios. 7.The compound according to claim 1 in which A, A′ each, independently ofone another, denote unbranched or branched alkyl having 1-10 C atoms, inwhich 1-2 non-adjacent CH₂ groups may be replaced by O, NH, NMe or NEt,and/or, in addition, 1-5 H atoms may be replaced by F and/or Cl, orcyclic alkyl having 3-8 C atoms, or pharmaceutically usable salts,tautomers or stereoisomers thereof, including mixtures thereof in allratios.
 8. The compound according to claim 1 in which R¹ and R²,together with the N atom to which they are bonded, denote anunsubstituted saturated, unsaturated or aromatic mono- or bicyclicheterocycle, which may contain a further 1 to 2 N, O and/or S atoms, R³and R⁴, together with the C atom to which they are bonded, denote anunsubstituted saturated monocyclic C3-C6-carbocycle, which may contain afurther 1 to 3 N, O and/or S atoms, X denotes CONR⁵R⁶, COOR⁵, COHet¹,Het¹, CONH(CH₂)_(p)CN or CONH(CH₂)_(p)NR⁵R⁶, Het denotes pyridyl,pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl,oxazolyl, isoxazolyl, thiazolyl, piperazinyl, pyrazinyl, pyridazinyl,morpholinyl, azepanyl, azetidinyl, pyrrolidinyl or piperidinyl, each ofwhich is unsubstituted or mono-, di- or trisubstituted by A, OA, OH,Hal, CN and/or ═O (carbonyl oxygen), A, A′ each, independently of oneanother, denote unbranched or branched alkyl having 1-10 C atoms, inwhich 1-2 non-adjacent CH₂ groups may be replaced by O, NH, NMe or NEt,and/or, in addition, 1-5 H atoms may be replaced by F and/or Cl, orcyclic alkyl having 3-8 C atoms, Hal denotes F, Cl, Br or I, n denotes0, 1, 2, 3 or 4, p denotes 1, 2, 3 or 4, or pharmaceutically usablesalts, tautomers or stereoisomers thereof, including mixtures thereof inall ratios.
 9. The compound according to claim 1, that is Com- pound No.Name and/or structure “A5”1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-cyclobutanecarboxamide “A20”1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-tert-butylcyclopropanecarboxamide “A21”1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethylcyclopropanecarboxamide “A22”1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N,N-dimethylcyclopropanecarboxamide “A23”1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethyl-N-methylcyclopropanecarboxamide “A24”1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N,N-diethylcyclopropanecarboxamide “A25”1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-(2-hydroxyethyl)-N-methylcyclopropanecarboxamide “A26”1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-(2-hydroxyethyl)-N-ethylcyclopropanecarboxamide “A27”[2-Amino-6-[1-(pyrrolidine-1-carbonyl)cyclo-propyl]quinazolin-4-yl]isoindolin-2-ylmethanone “A28”1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-(2-dimethylaminoethyl)-N-ethylcyclopropanecarboxamide “A29”1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-tert-butylcyclobutanecarboxamide “A30”1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethylcyclobutanecarboxamide “A31”1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-methylcyclobutanecarboxamide “A32”1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-propylcyclobutanecarboxamide “A33”1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-(2-amino-2-oxoethyl)cyclobutanecarboxamide “A34”1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-isobutylcyclobutanecarboxamide “A53”1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethylcyclopentanecarboxamide “A54”1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethyltetrahydropyran-4-carboxamide “A56” Ethyl1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-cyclopropanecarboxylate “A57”1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-cyclopropanecarboxylic acid “A61”1-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-cyclobutanecarboxylic acid “A68”2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-cyclopentanecarboxylic acid “A69”2-[2-Amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-tetrahydropyran-4-carboxylic acid “A77”N-Dimethyl-2-amino-6-(1-ethylcarbamoylcyclo-butyl)quinazoline-4-carboxamide “A78”N-Methylpropyl-2-amino-6-(1-ethylcarbamoylcyclobutyl)-quinazoline-4-carboxamide “A79”N-Diethyl-2-amino-6-(1-ethylcarbamoylcyclo-butyl)quinazoline-4-carboxamide “A80”N-Benzylmethyl-2-amino-6-(1-ethylcarbamoylcyclobutyl)-quinazoline-4-carboxamide “A87” Ethyl1-(2-amino-4-dimethylcarbamoylquinazolin-6-yl)- cyclobutanecarboxylate

or pharmaceutically usable salts, tautomers or stereoisomers thereof,including mixtures thereof in all ratios.
 10. A process for thepreparation of compounds of the formula I according to claim 1 orpharmaceutically usable salts, tautomers or stereoisomers thereof,comprising a) preparing a compound of formula I in which X denotes COOA,by reacting a compound of formula II

in which R¹, R², R³ and R⁴ have the meanings indicated in claim 1, Rdenotes an amino-protecting group, X denotes COOA, and A has the meaningindicated in claim 1, with a compound of formula IIIY₃Si—N═C═N—SiY₃  III in which Y denotes alkyl having 1-4 C atoms, andoptionally b) converting a radical X into another radical X by i)hydrolyzing an ester or ii) converting an acid into an amide using anamine, c) optionally converting a base or acid of formula I into one ofits salts.
 11. A pharmaceutical composition comprising at least onecompound according to claim 1 and/or pharmaceutically usable salts,tautomers or stereoisomers thereof, including mixtures thereof in allratios, and a pharmaceutically acceptable carrier.
 12. A pharmaceuticalcomposition comprising at least one compound according to claim 1 and/orpharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios, and at least one furthermedicament active ingredient.
 13. A kit comprising separate packs of (a)an effective amount of a compound according to claim 1 and/orpharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios, and (b) an effective amount ofa further medicament active ingredient.